Modulators of the beta-3 adrenergic receptor useful for the treatment or prevention of disorders related thereto

ABSTRACT

The present invention relates to compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the beta-3 adrenergic receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of a beta-3 adrenergic receptor-mediated disorder, such as, heart failure; cardiac performance in heart failure; mortality, reinfarction, and/or hospitalization in connection with heart failure; acute heart failure; acute decompensated heart failure; congestive heart failure; severe congestive heart failure; organ damage associated with heart failure (e.g., kidney damage or failure, heart valve problems, heart rhythm problems, and/or liver damage); heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; cardiovascular mortality following myocardial infarction; cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction; left ventricular failure; left ventricular dysfunction; class II heart failure using the New York Heart Association (NYHA) classification system; class III heart failure using the New York Heart Association (NYHA) classification system; class IV heart failure using the New York Heart Association (NYHA) classification system; LVEF&lt;40% by radionuclide ventriculography; LVEF≤35% by echocardiography or ventricular contrast angiography; and conditions related thereto.

FIELD OF THE INVENTION

The present invention relates to compounds of Formula (Ia) andpharmaceutical compositions thereof that modulate the activity of thebeta-3 adrenergic receptor. Compounds of the present invention andpharmaceutical compositions thereof are directed to methods useful inthe treatment of a beta-3 adrenergic receptor-mediated disorder, suchas, heart failure; cardiac performance in heart failure; mortality,reinfarction, and/or hospitalization in connection with heart failure;acute heart failure; acute decompensated heart failure; congestive heartfailure; severe congestive heart failure; organ damage associated withheart failure (e.g., kidney damage or failure, heart valve problems,heart rhythm problems, and/or liver damage); heart failure due to leftventricular dysfunction; heart failure with normal ejection fraction;cardiovascular mortality following myocardial infarction; cardiovascularmortality in patients with left ventricular failure or left ventriculardysfunction; left ventricular failure; left ventricular dysfunction;class II heart failure using the New York Heart Association (NYHA)classification system; class III heart failure using the New York HeartAssociation (NYHA) classification system; class IV heart failure usingthe New York Heart Association (NYHA) classification system; leftventricular ejection fraction (LVEF)<40% by radionuclideventriculography; LVEF≤35% by echocardiography or ventricular contrastangiography; and conditions related thereto.

BACKGROUND OF THE INVENTION

Acute heart failure is a rapid decline in heart function that can causeanoxia of tissues (particularly the brain), leading to death. Acuteheart failure can occur in previously asymptomatic individuals (e.g.,individuals with pulmonary edema or cardiogenic shock), or inindividuals with an acute exacerbation of chronic heart failure.

In the healthy heart, the actions of beta-1 and beta-2 adrenergicreceptors are dominant and act through a Gs-coupled pathway to increasethe force and frequency of myocardial contraction, while beta-3adrenergic receptors act through a Gi-coupled eNOS pathway to exert weaknegative inotropic effects. In the failing heart, beta-1 and beta-2adrenergic receptors are downregulated or desensitized, while beta-3adrenergic receptors are upregulated, thereby emphasizing the negativeeffects of beta-3 agonism on cardiac contractility. Morimoto, Am JPhysiol Heart Circ Physiol, 286: H2425-H2433, 2004; Kulandavelu, J AmCollege Cardiology 59(22): 1988-90, 2012.

In individuals experiencing acute heart failure, the short-term goal isto increase contractility and improve hemodynamic status. The currentstandard of care for acute heart failure includes the administration ofinotropesagents that alter the force or energy of cardiac contractions.These agents are typically administered in an intensive care setting bycontinuous injection. Examples of such agents include adrenaline,dobutamine, dopamine, levosimendan, and noradrenaline. However, theinitial improvement in contractility afforded by these agents can befollowed by accelerated mortality. Katz A M and Konstam M A, HeartFailure: Pathophysiology, Molecular Biology and Clinical Management,Lippincott, Williams & Wilkins, 2nd edition, 1999. The excessivemortality following administration of these agents has been linked toincreased tachycardia and myocardial oxygen consumption that leads toarrhythmia and myocardial ischemia. Francis et al., J Am College ofCardiology 63(20): 2069-2078, 2014.

SUMMARY OF THE INVENTION

One aspect of the present invention encompasses certain1-oxa-8-azaspiro[4.5]decan-3-yl-aminopropanyl-ether derivatives selectedfrom compounds of Formula (Ia) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

wherein:

X is —SO₂—, —C(═O)—, or —CH₂C(═O)—;

W is absent or C₁-C₃ alkylene;

R¹ is aryl or heteroaryl, wherein each is optionally substituted withone or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,amino, cyano, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen, hydroxyl, oxo,and sulfamoyl; and wherein said C₁-C₆ alkyl and C₃-C₇ cycloalkyl areeach optionally substituted with one or more substituents selected from:amino, C₁-C₆ alkoxy, C₁-C₆ alkylcarboxamide, —Y—C₃-C₇-cycloalkyl,—Y—C₁-C₆-alkylene-Z, C₁-C₆ alkylamino, C₁-C₆ haloalkylamino, andheterocyclyl;

Y is independently selected from: —O—, —NH—, and —N—(C₁-C₄ alkyl)-;

Z is independently selected from: hydroxyl, C₁-C₆ alkoxy, amino, C₁-C₆alkylamino, and C₂-C₆ dialkylamino;

R² is selected from: C₂-C₆ alkenyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,heterocyclyl, and C₁-C₆ haloalkyl; each optionally substituted with oneor more substituents selected from: C₁-C₆ alkoxy, C₁-C₆alkylenehydroxyl, amino, aryl, C₃-C₇ cycloalkyl, cyano, C₃-C₇halocycloalkyl, hydroxyl, and oxo; and

R^(3a), R^(3b), R^(3c), and R^(3d) are each independently H or halogen.

One aspect of the present invention relates to pharmaceutical productsselected from: a pharmaceutical composition, a formulation, a unitdosage form, and a kit; each comprising a compound of the presentinvention.

One aspect of the present invention relates to pharmaceuticalcompositions comprising a compound of the present invention, and apharmaceutically acceptable carrier.

One aspect of the present invention relates to methods for preparingpharmaceutical compositions comprising the step of admixing a compoundof the present invention and a pharmaceutically acceptable carrier.

One aspect of the present invention relates to methods for treating orpreventing a beta-3 adrenergic receptor-mediated disorder in anindividual, comprising administering to the individual in need thereof,a therapeutically effective amount of a compound of the presentinvention; a pharmaceutical product of the present invention; or apharmaceutical composition of the present invention.

One aspect of the present invention relates to methods for treating orpreventing heart failure in an individual, comprising administering tothe individual in need thereof, a therapeutically effective amount of acompound of the present invention; a pharmaceutical product of thepresent invention; or a pharmaceutical composition of the presentinvention.

One aspect of the present invention relates to methods for treating ahypotensive patient, comprising administering to the patient in needthereof, a therapeutically effective amount of a compound of the presentinvention; a pharmaceutical product of the present invention; or apharmaceutical composition of the present invention.

One aspect of the present invention relates to methods for treating aborderline hypotensive patient, comprising administering to the patientin need thereof, a therapeutically effective amount of a compound of thepresent invention; a pharmaceutical product of the present invention; ora pharmaceutical composition of the present invention.

One aspect of the present invention relates to methods for treating anormotensive patient, comprising administering to the patient in needthereof, a therapeutically effective amount of a compound of the presentinvention; a pharmaceutical product of the present invention; or apharmaceutical composition of the present invention.

One aspect of the present invention relates to methods for treating ahypertensive patient, comprising administering to the patient in needthereof, a therapeutically effective amount of a compound of the presentinvention; a pharmaceutical product of the present invention; or apharmaceutical composition of the present invention.

One aspect of the present invention relates to methods for treating apatient following myocardial infarction, comprising administering to thepatient in need thereof, a therapeutically effective amount of acompound of the present invention; a pharmaceutical product of thepresent invention; or a pharmaceutical composition of the presentinvention.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating orpreventing a beta-3 adrenergic receptor-mediated disorder in anindividual.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating orpreventing heart failure in an individual.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating ahypotensive patient.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating aborderline hypotensive patient.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating anormotensive patient.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating ahypertensive patient.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating apatient following myocardial infarction.

One aspect of the present invention relates to compounds of the presentinvention; a pharmaceutical product of the present invention; or apharmaceutical composition of the present invention; for use in a methodof treatment of the human or animal body by therapy.

One aspect of the present invention relates to compounds of the presentinvention; pharmaceutical products of the present invention; orpharmaceutical compositions of the present invention; for use in amethod for treating or preventing a beta-3 adrenergic receptor-mediateddisorder in an individual.

One aspect of the present invention relates to compounds of the presentinvention; pharmaceutical products of the present invention; orpharmaceutical compositions of the present invention; for use in amethod for treating or preventing heart failure in an individual.

One aspect of the present invention relates to compounds of the presentinvention; pharmaceutical products of the present invention; orpharmaceutical compositions of the present invention; for use in amethod for treating a hypotensive patient.

One aspect of the present invention relates to compounds of the presentinvention; pharmaceutical products of the present invention; orpharmaceutical compositions of the present invention; for use in amethod for treating a borderline hypotensive patient.

One aspect of the present invention relates to compounds of the presentinvention; pharmaceutical products of the present invention; orpharmaceutical compositions of the present invention; for use in amethod for treating a normotensive patient.

One aspect of the present invention relates to compounds of the presentinvention; pharmaceutical products of the present invention; orpharmaceutical compositions of the present invention; for use in amethod for treating a hypertensive patient.

One aspect of the present invention relates to compounds of the presentinvention; pharmaceutical products of the present invention; orpharmaceutical compositions of the present invention; for use in amethod for treating a patient following myocardial infarction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isselected from the list consisting of: heart failure; cardiac performancein heart failure; mortality, reinfarction, and/or hospitalization inconnection with heart failure; acute heart failure; acute decompensatedheart failure; congestive heart failure; severe congestive heartfailure; organ damage associated with heart failure (e.g., kidney damageor failure, heart valve problems, heart rhythm problems, and/or liverdamage); heart failure due to left ventricular dysfunction; heartfailure with normal ejection fraction; cardiovascular mortalityfollowing myocardial infarction; cardiovascular mortality in patientswith left ventricular failure or left ventricular dysfunction; leftventricular failure; left ventricular dysfunction; class II heartfailure using the New York Heart Association (NYHA) classificationsystem; class III heart failure using the New York Heart Association(NYHA) classification system; class IV heart failure using the New YorkHeart Association (NYHA) classification system; LVEF<40% by radionuclideventriculography; and LVEF≤35% by echocardiography or ventricularcontrast angiography.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isheart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isreduced cardiac performance in heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder ismortality, reinfarction, and/or hospitalization in connection with heartfailure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isacute heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isacute decompensated heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder iscongestive heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder issevere congestive heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isorgan damage associated with heart failure (e.g., kidney damage orfailure, heart valve problems, heart rhythm problems, and/or liverdamage).

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isheart failure due to left ventricular dysfunction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isheart failure with normal ejection fraction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder iscardiovascular mortality following myocardial infarction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder iscardiovascular mortality in patients with left ventricular failure orleft ventricular dysfunction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isleft ventricular failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isleft ventricular dysfunction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isclass II heart failure using the New York Heart Association (NYHA)classification system.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isclass III heart failure using the New York Heart Association (NYHA)classification system.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isclass IV heart failure using the New York Heart Association (NYHA)classification system.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isleft ventricular ejection fraction (LVEF)<40% by radionuclideventriculography.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isleft ventricular ejection fraction (LVEF)≤35% by echocardiography orventricular contrast angiography.

Described herein are beta-3 adrenergic receptor antagonists that areuseful for boosting contractility of the heart. These compounds areselective for the beta-3 adrenergic receptor and have a distinctmechanism of action that differs from currently prescribed inotropeswith known cardiotoxic effects.

Because increased beta-3 adrenergic receptor activity is known toinhibit contractility in the failing heart, studies were conducted toevaluate the effect of beta-3 adrenergic receptor antagonists oncontractile function. As described herein, these studies demonstratethat the inhibition of the beta-3 adrenergic receptor by beta-3adrenergic receptor antagonists improves contractile function andhemodynamic status in the failing heart. There is a need for new agentsthat increase cardiac contractility while avoiding cardiotoxic effects.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a general synthetic scheme for the preparation ofintermediates useful in preparing Compounds of Formula (Ia), wherein PG¹(i.e., Protecting Group 1) can be a variety of protecting groups knownto one skilled in the art, such as, a benzyloxy carbamate group.

FIG. 2 shows a general synthetic scheme for the preparation ofintermediates useful in preparing Compounds of Formula (Ia), wherein PG¹(Protecting Group 1) and PG² (Protecting Group 2) can be a variety ofprotecting groups known to one skilled in the art, such as, a benzyloxycarbamate (Cbz) group and a tert-butoxycarbonyl (BOC) group. In certaininstances, PG¹ and PG² are different and are orthogonal protectinggroups, such as, PG¹ is Cbz and PG² is BOC.

FIG. 3 shows a general synthetic scheme for the preparation of Compoundsof Formula (Ia). It is understood that one or more chiral intermediatescan be used in the scheme to provide chiral compounds of Formula (Ia).

FIG. 4 shows a general synthetic scheme for the preparation of Compoundsof Formula (Ia). It is understood that one or more chiral intermediatescan be used in the scheme to provide chiral compounds of Formula (Ia).PG¹ and PG² are protecting groups such as, BOC (tert-butyloxycarbonyl),Cbz (carboxybenzyl or alternatively named benzyloxy carbamate) and thelike.

FIG. 5 shows a general synthetic scheme for the preparation of Compoundsof Formula (Ia). It is understood that one or more chiral intermediatescan be used in the scheme to provide chiral compounds of Formula (Ia).

FIG. 6 shows a general synthetic scheme for the preparation of Compoundsof Formula (Ia) utilizing a chiral oxirane.

FIG. 7 shows a general synthetic scheme for the preparation of Compoundsof Formula (Ia) utilizing a chiral oxirane and a chiral amineintermediate (see FIG. 2).

FIG. 8 shows a general synthetic scheme for the preparation of Compoundsof Formula (Ia) utilizing a chiral oxirane and a chiral amineintermediate (see FIG. 2).

FIG. 9 shows a general synthetic scheme for the preparation of Compoundsof Formula (Ia) utilizing a chiral oxirane and a chiral amineintermediate (see FIG. 2).

FIG. 10 shows a general synthetic scheme for the preparation ofCompounds of Formula (Ia) utilizing a chiral oxirane and a chiral amineintermediate (see FIG. 2).

FIG. 11 shows a general synthetic scheme for the preparation ofCompounds of Formula (Ia). It is understood that one or more chiralintermediates can be used in the scheme to provide chiral compounds ofFormula (Ia).

FIG. 12 shows a general synthetic scheme for the preparation ofCompounds of Formula (Ia). It is understood that one or more chiralintermediates can be used in the scheme to provide chiral compounds ofFormula (Ia).

FIG. 13 shows a general synthetic scheme for the preparation ofCompounds of Formula (Ia). It is understood that one or more chiralintermediates can be used in the scheme to provide chiral compounds ofFormula (Ia).

FIG. 14 shows three general synthetic schemes for the preparation ofcertain Compounds of Formula (Ia) wherein X is —SO₂—, —C(═O)—, and—CH₂C(═O)—. It is understood that the intermediates can be chiralproviding chiral compounds of Formula (Ia).

FIG. 15 shows a general synthetic scheme for the preparation of certainintermediates useful in preparing Compounds of Formula (Ia).

FIG. 16 shows a general synthetic scheme for the preparation of certainintermediates useful in preparing Compounds of Formula (Ia).

FIG. 17 shows a general synthetic scheme for the preparation of certainintermediates useful in preparing Compounds of Formula (Ia).

FIG. 18 shows a general synthetic scheme for the preparation of certainintermediates useful in preparing Compounds of Formula (Ia).

FIG. 19 shows a general synthetic scheme for the preparation of certainCompounds of Formula (Ia) wherein R¹ is —Ar¹—Ar². It is understood thatAr¹ and Ar² can be optionally substituted with one or more groups asdescribed herein.

FIG. 20 shows a general synthetic scheme for the preparation of certainCompounds of Formula (Ia) wherein R¹ is —Ar¹—Ar². The schemespecifically shows Ar² substituted with at least —CH₂OH or —CH₂NH—C₁-C₆alkyl. It is understood that Ar¹ and Ar² (excluding the ring atom forAr² that is bonded to either —CH₂OH or —CH₂NH—C₁-C₆ alkyl) can beoptionally substituted with one or more groups as described herein.

FIG. 21 shows a general synthetic scheme for the preparation of certainCompounds of Formula (Ia) wherein R¹ is —Ar¹—Ar². The schemespecifically shows Ar² substituted with at least —CH₂NH₂. It isunderstood that Ar¹ and Ar² (excluding the ring atom for Ar² that isbonded to —CH₂NH₂) can be optionally substituted with one or more groupsas described herein.

FIG. 22 shows a general synthetic scheme for the preparation of certainCompounds of Formula (Ia) wherein R¹ is —Ar¹—Ar². The schemespecifically shows Ar² substituted with at least —C(═O)H or —CH₂NH—C₁-C₆alkyl. It is understood that Ar¹ and Ar² (excluding the ring atom forAr² that is bonded to either —C(═O)H or —CH₂NH—C₁-C₆ alkyl) can beoptionally substituted with one or more groups as described herein.

FIG. 23 shows a general synthetic scheme for the preparation of certainCompounds of Formula (Ia) wherein R¹ is 4-hydroxy-quinolin-3-yl (or atautomer related thereto, such as, 4-oxo-1,4-dihydroquinolin-3-yl) or1-(C₁-C₆-alkyl)-4-oxo-1,4-dihydroquinolin-3-yl, such as,1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl. It is understood that R^(23a),R^(23b), R^(23c), and R^(23d) can be C₁-C₆ alkoxy, C₁-C₆ alkyl, amino,cyano, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen, hydroxyl, oxo, andsulfamoyl, and the C₁-C₆ alkyl and C₃-C₇ cycloalkyl each can beoptionally substituted with one or more substituents selected from:amino, C₁-C₆ alkoxy, C₁-C₆ alkylcarboxamide, —Y—C₃-C₇-cycloalkyl,—Y—C₁-C₆-alkylene-Z, C₁-C₆ alkylamino, C₁-C₆ haloalkylamino, andheterocyclyl, wherein Y and Z are as defined herein.

FIG. 24 shows a general synthetic scheme for introducing R² intoCompounds of Formula (Ia) wherein W is a bond.

FIG. 25 shows the scheme for administration of compounds of the presentinvention in normal rats in Example 4.

FIG. 26 shows the scheme for administration of compounds of the presentinvention in heart failure rats in Example 4.

FIG. 27 shows the inhibition of negative effects of BRL on LVP in normalrats following the administration of Compound 123 (Example 4).

FIG. 28 shows the inhibition of negative effects of BRL on LVP in normalrats following the administration of Compound 310 (Example 4).

FIG. 29 shows the inhibition of negative effects of BRL on LVP in normalrats following the administration of Compound 163 (Example 4).

FIG. 30 shows the inhibition of negative effects of BRL on LVP in normalrats following the administration of Compound 154 (Example 4).

FIG. 31 shows the inhibition of negative effects of BRL on LVP in normalrats following the administration of Compound 88 (Example 4).

FIG. 32 shows the inhibition of negative effects of BRL on LVP in a ratwith heart failure following the administration of Compound 88 (Example4).

FIG. 33A show an example of the effect of Compound 88 in a dog prior toheart failure.

FIG. 33B show an example of the effect of Compound 88 in a dog followingheart failure. The horizontal dashed line in the graphs is the baselineLV pressure indicating the presence of heart failure (compare the lowerLV pressures in FIG. 33A and the baseline LV pressure in FIG. 33B).

FIG. 34 shows the effect of Compound 88 on hemodynamics and LVcontractility in normal dogs (n=4).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

For clarity and consistency, the following definitions will be usedthroughout this patent document.

As used herein, “administering” refers to providing a compound of theinvention or other therapy, remedy or treatment to the individual inneed of treatment in a form that can be introduced into thatindividual's body in a therapeutically useful form and therapeuticallyuseful amount, including, but not limited to: oral dosage forms, such astablets, capsules, syrups, suspensions, and the like; injectable dosageforms, such as IV, IM, or IP, and the like; transdermal dosage forms,including creams, jellies, powders, or patches; buccal dosage forms;inhalation powders, sprays, suspensions, and the like; and rectalsuppositories. A health care practitioner can directly provide acompound to an individual in the form of a sample, or can indirectlyprovide a compound to an individual by providing an oral or writtenprescription for the compound. Also, for example, an individual canobtain a compound by themselves without the involvement of a health carepractitioner. When the compound is administered to the individual, thebody is transformed by the compound in some way. When a compound of theinvention is provided in combination with one or more other agents,“administration” is understood to include the compound and other agentsare administered at the same time or at different times. When the agentsof a combination are administered at the same time, they can beadministered together in a single composition or they can beadministered separately.

The term “antagonist” as used herein” refers to a moiety that cancompetitively bind to the β₃-adrenergic receptor as an agonist (forexample, the endogenous ligand) but does not activate or substantiallyreduces the intracellular response compared to an agonist, and canthereby inhibit the intracellular responses by an agonist or partialagonist. An “antagonist” does not diminish the baseline intracellularresponse, or does so to a negligible extent, in the absence of anagonist or partial agonist.

The term “composition” refers to a compound or crystalline form thereof,including but not limited to, salts, solvates, and hydrates of acompound of the present invention, in combination with at least oneadditional component, such as, a composition obtained/prepared duringsynthesis, preformulation, in-process testing (i.e., TLC, HPLC, NMRsamples), and the like.

The term “hydrate” as used herein means a compound of the invention or asalt thereof that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

The term “in need of treatment” and the term “in need thereof” whenreferring to treatment are used interchangeably to mean a judgment madeby a caregiver (e.g. physician, nurse, nurse practitioner, etc. in thecase of humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the compoundsof the invention. Accordingly, the compounds of the invention can beused in a protective or preventive manner; or compounds of the inventioncan be used to alleviate, inhibit, or ameliorate the disease, condition,or disorder.

The term “individual” refers to any animal, including mammals, such as,mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, primates, and humans. In some embodiment “individual” refers tohumans.

The term “pharmaceutical composition” refers to a specific compositioncomprising at least one active ingredient; including but not limited to,salts, solvates, and hydrates of compounds of the present invention,whereby the composition is amenable to investigation for a specified,efficacious outcome in a mammal (for example, without limitation, ahuman). Those of ordinary skill in the art will understand andappreciate the techniques appropriate for determining whether an activeingredient has a desired efficacious outcome based upon the needs of theartisan.

The phrase “pharmaceutically acceptable salts, solvates, and hydrates”when referring to a compound/compounds as described herein embracespharmaceutically acceptable solvates and/or hydrates of thecompound/compounds, pharmaceutically acceptable salts of thecompound/compounds, as well as pharmaceutically acceptable solvatesand/or hydrates of pharmaceutically acceptable salts of thecompound/compounds. It is also understood that when the phrase“pharmaceutically acceptable solvates and hydrates” or the phrase“pharmaceutically acceptable solvate or hydrate” is used when referringto a compound/compounds as described herein that are salts, it embracespharmaceutically acceptable solvates and/or hydrates of such salts. Itis also understood by a person of ordinary skill in the art thathydrates are a subgenus of solvates.

The term “prescribing” refers to order, authorize, or recommend the useof a drug or other therapy, remedy, or treatment. In some embodiments, ahealth care provider orally advises, recommends, or authorizes the useof a compound, dosage regimen, or other treatment to an individual. Thehealth care provider may or may not provide a written prescription forthe compound, dosage regimen, or treatment. Further, the health careprovider may or may not provide the compound or treatment to theindividual. For example, the health care provider can advise theindividual where to obtain the compound without providing the compound.In some embodiments, a health care provider can provide a writtenprescription for the compound, dosage regimen, or treatment to theindividual. A prescription can be written on paper or recorded onelectronic media. In addition, a prescription can be called in (oral) orfaxed in (written) to a pharmacy or a dispensary. In some embodiments, asample of the compound or treatment is given to the individual. As usedherein, giving a sample of a compound constitutes an implicitprescription for the compound. Different health care systems around theworld use different methods for prescribing and administering compoundsor treatments, and these methods are encompassed by the disclosureherein.

A health care provider can include, for example, a physician, nurse,nurse practitioner, or other health care professional who can prescribeor administer compounds (drugs) for the disorders disclosed herein. Inaddition, a health care provider can include anyone who can recommend,prescribe, administer, or prevent an individual from receiving acompound or drug, including, for example, an insurance provider.

The terms “prevent,” “preventing,” and “prevention” refer to theelimination or reduction of the occurrence or onset of one or moresymptoms associated with a particular disorder. For example, the terms“prevent,” “preventing,” and “prevention” can refer to theadministration of therapy on a prophylactic or preventative basis to anindividual who may ultimately manifest at least one symptom of adisorder but who has not yet done so. Such individuals can be identifiedon the basis of risk factors that are known to correlate with thesubsequent occurrence of the disease, such as the presence of abiomarker. Alternatively, prevention therapy can be administered as aprophylactic measure without prior identification of a risk factor.Delaying the onset of the at least one episode and/or symptom of adisorder can also be considered prevention or prophylaxis.

The term “solvate” as used herein means a compound of the invention or asalt thereof that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

The terms “treat,” “treating,” and “treatment” refer to theadministration of therapy to an individual who already manifests, or whohas previously manifested, at least one symptom of a disease, disorder,condition, dependence, or behavior. For example, “treating” can includeany of the following with respect to a disease, disorder, condition,dependence, or behavior: alleviating, abating, ameliorating, improving,inhibiting (e.g., arresting the development), relieving, or causingregression. “Treating” can also include treating the symptoms,preventing additional symptoms, preventing the underlying physiologicalcauses of the symptoms, or stopping the symptoms (eitherprophylactically and/or therapeutically) of a disease, disorder,condition, dependence, or behavior. For example, the term “treating” inreference to a disorder means a reduction in severity of one or moresymptoms associated with a particular disorder. Therefore, treating adisorder does not necessarily mean a reduction in severity of allsymptoms associated with a disorder and does not necessarily mean acomplete reduction in the severity of one or more symptoms associatedwith a disorder.

The term “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, or human that is beingsought by an individual, researcher, veterinarian, medical doctor, orother clinician or caregiver, which can include one or more of thefollowing:

(1) preventing the disorder, for example, preventing a disease,condition, or disorder in an individual who may be predisposed to thedisease, condition, or disorder but does not yet experience or displaythe relevant pathology or symptomatology;

(2) inhibiting the disorder, for example, inhibiting a disease,condition, or disorder in an individual who is experiencing ordisplaying the relevant pathology or symptomatology (i.e., arrestingfurther development of the pathology and/or symptomatology); and

(3) ameliorating the disorder, for example, ameliorating a disease,condition, or disorder in an individual who is experiencing ordisplaying the relevant pathology or symptomatology (i.e., reversing thepathology and/or symptomatology).

Chemical Group, Moiety or Radical

The term “C₂-C₆ alkenyl” denotes a radical containing 2 to 6 carbonswherein at least one carbon-carbon double bond is present. Someembodiments contain 2 to 5 carbons. Some embodiments contain 2 to 4carbons. Some embodiments contain 2 to 3 carbons. Some embodimentscontain 2 carbons (i.e., —CH═CH₂). Both E and Z isomers are embraced bythe term “alkenyl.” Furthermore, the term “alkenyl” includes di- andtri-alkenyls.

The terms “C₁-C₆ alkylene” and “C₁-C₄ alkylene” refers to a straight orbranched, saturated aliphatic, divalent radical having the definednumber of carbons, 1 to 6 carbon atoms or 1 to 4 carbon atomsrespectively. Some embodiments contain 1 to 2 carbons. Some embodimentscontain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Someembodiments contain 1 to 3 carbons. Some embodiments contain 1 or 2carbons. Some embodiments contain 1 carbon atom (i.e., —CH₂—). Examplesinclude, but are not limited to, methylene, ethylene, n-propylene,isopropylene, n-butylene, s-butylene, isobutylene, t-butylene,pentylene, isopentylene, t-pentylene, neopentylene, 1-methylbutylene[i.e., —CH(CH₃)CH₂CH₂CH₃], 2-methylbutylene [i.e., —CH₂CH(CH₃)CH₂CH₃],n-hexylene, and the like.

The term “amino” refers to the group —NH₂.

The term “aryl” refers to a ring system containing 6 to 12 carbon atomsthat may contain a single ring, two fused rings, or two rings bonded bya single bond (i.e., biphenyl) and wherein at least one ring isaromatic. Examples include phenyl, biphenyl, indanyl,tetrahydronaphthalenyl, naphthalenyl, and the like. Examples of biphenylinclude: [1,1′-biphenyl]-2-yl (i.e., biphenyl-2-yl),[1,1′-biphenyl]-3-yl (i.e., biphenyl-3-yl), or [1,1′-biphenyl]-4-yl(i.e., biphenyl-4-yl) with the following structures respectively:

When a substituent is present on the aryl ring, the substituent can bebonded at any available ring carbon.

The term “C₁-C₆ alkoxy” refers to a radical comprising a C₁-C₆ alkylgroup attached directly to an oxygen atom, wherein C₁-C₆ alkyl has thesame definition as found herein. Some embodiments contain 1 to 5 carbons(i.e., C₁-C₅ alkoxy). Some embodiments contain 1 to 4 carbons (i.e.,C₁-C₄ alkoxy). Some embodiments contain 1 to 3 carbons (i.e., C₁-C₃alkoxy). Some embodiments contain 1 or 2 carbons. Examples include, butare not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,t-butoxy, isobutoxy, s-butoxy, and the like.

The term “C₁-C₆ alkyl” refers to a straight or branched carbon radicalcontaining 1 to 6 carbons. Some embodiments are 1 to 5 carbons (i.e.,C₁-C₅ alkyl), some embodiments are 1 to 4 carbons (i.e., C₁-C₄ alkyl),some embodiments are 1 to 3 carbons (i.e., C₁-C₃ alkyl), and someembodiments are 1 or 2 carbons. Examples of an alkyl include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neo-pentyl,1-methylbutyl [i.e., —CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e.,—CH₂CH(CH₃)CH₂CH₃], n-hexyl and the like.

The term “C₁-C₆ alkylamino” refers to mean a radical comprising oneC₁-C₆ alkyl group attached to an NH group, wherein C₁-C₆ alkyl has thesame meaning as described herein. Some embodiments are “C₁-C₂alkylamino.” Some examples include methylamino, ethylamino,n-propylamino, isopropylamino, n-butylamino, s-butylamino,isobutylamino, t-butylamino, and the like.

The term “C₁-C₆ alkylcarboxamide” refers to mean a single C₁-C₆ alkylgroup attached to either the carbon or the nitrogen of an amide group,wherein C₁-C₆ alkyl has the same definition as found herein. The C₁-C₆alkylcarboxamido group may be represented by the following:

Examples include, N-methylcarboxamide, N-ethylcarboxamide,N-n-propylcarboxamide, N-isopropylcarboxamide, N-n-butylcarboxamide,N-s-butylcarboxamide, N-isobutylcarboxamide, N-t-butylcarboxamide, andthe like.

The term “cyano” refers to the group —CN.

The term “C₃-C₇ cycloalkyl” refers to a saturated ring radicalcontaining 3 to 7 carbons. Some embodiments contain 3 to 6 carbons. Someembodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7carbons. Some embodiments contain 3 to 4 carbons. Examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike.

The term “C₂-C₆ dialkylamino” refers to a radical comprising an aminogroup substituted with two alkyl groups, the alkyl groups can be thesame or different provided that two alkyl groups do not exceed a totalof 6 carbon atoms between the two alkyl groups. Some embodiments areC₂-C₄ dialkylamino. Some examples include dimethylamino,methylethylamino, diethylamino, methylpropylamino, methylbutylamino,methylpentylamino, methylisopropylamino, ethylpropylamino,ethylisopropylamino, dipropylamino, propylisopropylamino, and the like.

The term “C₁-C₆ haloalkylamino” refers to a radical comprising one C₁-C₆haloalkyl group attached to an NH group, wherein C₁-C₆ haloalkyl has thesame meaning as described herein. Some embodiments are “C₁-C₂haloalkylamino.” Some examples include 2-fluoroethylamino,2,2,2-trifluoroethylamino, (1,1,1-trifluoropropan-2-yl)amino,3,3,3-trifluoropropylamino, 2,2,2-trifluoropropylamino, and the like.

The term “C₁-C₆ haloalkyl” refers to a radical comprising a C₁-C₆ alkylgroup substituted with one or more halogens, wherein C₁-C₆ alkyl has thesame definition as found herein. The C₁-C₆ haloalkyl may be fullysubstituted in which case it can be represented by the formulaC_(n)L_(2n+1), wherein L is a halogen and “n” is 1, 2, 3, 4, 5, or 6.When more than one halogen is present then they may be the same ordifferent and selected from: fluorine, chlorine, bromine, and iodine. Insome embodiments, haloalkyl contains 1 to 5 carbons (i.e., C₁-C₅haloalkyl). In some embodiments, haloalkyl contains 1 to 4 carbons(i.e., C₁-C₄ haloalkyl). In some embodiments, haloalkyl contains 1 to 3carbons (i.e., C₁-C₃ haloalkyl). In some embodiments, haloalkyl contains1 or 2 carbons. Examples of haloalkyl groups include fluoromethyl,difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl,2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, and thelike.

The term “C₃-C₇ halocycloalkyl” refers to a radical comprising a C₃-C₇cycloalkyl group substituted with one or more halogens, wherein C₃-C₇cycloalkyl has the same definition as found herein. Examples ofhalocycloalkyl groups include 2,2-difluorocyclopropyl,1-fluorocyclopropyl, 4,4-difluorocyclohexyl, and the like.

The term “halogen” refers to fluoro, chloro, bromo, or iodo group. Insome embodiments, halogen is fluoro, chloro, or bromo. In someembodiments, halogen is fluoro or chloro. In some embodiments, halogenis fluoro.

The term “heteroaryl” refers to a ring system containing 5 to 14 ringatoms, that may contain a single ring, two fused rings, two rings bondedby a single bond, or three fused rings, and wherein at least one ringatom is a heteroatom, such as, O, S, and N, wherein N is optionallysubstituted with H, C₁-C₄ acyl, or C₁-C₄ alkyl and at least one ring isaromatic. When a heteroaryl group is substituted with an oxo group, theoxo group can be on any available ring atom, for example, a ring carbonto form a carbonyl group, a ring nitrogen to form an N-oxide, and a ringsulfur to form either a sulfoxide (i.e., —S(═O)—) or a sulfone (i.e.,—S(═O)₂—). Some embodiments contain 5 to 6 ring atoms for examplefuranyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,and the like. Some embodiments contain 8 to 14 ring atoms for examplequinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl,indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl.phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl,1H-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl,isobenzofuran, 2,3-dihydrobenzofuranyl, 4H-benzo[1,3]dioxinyl,3,4-dihydro-1H-isoquinolinyl,1,4,6,7-tetrahydro-imidazo[4,5-c]pyridinyl,7,8-dihydro-5H-[1,6]naphthyridinyl,5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, benzo[1,3]dioxolyl,pyrazolo[1,5-a]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, and the like.When the “heteroaryl” is a ring system containing two rings bonded by asingle bond it is understood that the two rings can be bonded at anyavailable ring carbon or available nitrogen atom. Some embodimentsinclude 3-(1H-pyrazol-4-yl)phenyl, 3-(pyridin-4-yl)phenyl,3-(pyridin-2-yl)phenyl, 5-phenylthiophen-2-yl, 3-(pyridin-3-yl)phenyl,3-(pyrimidin-5-yl)phenyl, 5-(phenyl)pyridin-3-yl,5-(1H-pyrazol-4-yl)pyridin-3-yl, 4-(pyridin-3-yl)phenyl,4-(pyridin-4-yl)phenyl, 4-(pyridin-2-yl)phenyl, (corresponding to thefollowing chemical structures) and the like.

In some embodiments, “heteroaryl” is selected from the group:(1H-pyrazolyl)phenyl, (1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl,(pyrimidinyl)phenyl, 1,2,3,4-tetrahydropyrido[3,2-b]pyrazinyl,1,2-dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl,1H-indazolyl, 1H-indolyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl,1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl,2,3-dihydro-1H-imidazo[4,5-b]pyridinyl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,3,4-dihydro-2H-pyrano[2,3-b]pyridinyl,3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl,(phenyl)pyridinyl, 5,6,7,8-tetrahydroquinolinyl,6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl,benzofuranyl, chromanyl, isoquinolinyl, isoxazolyl, phenylthiophenyl,pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl, and thiazolyl. In someembodiments, “heteroaryl” is selected from the group:1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl, 1,2-dihydroquinolin-6-yl,1,4-dihydroquinolin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl,1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl,1H-pyrazol-4-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl,1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,4-dihydroquinolin-3-yl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 2,3-dihydrobenzofuran-5-yl,3-(1H-pyrazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl,3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl,3-(pyrimidin-5-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl,3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl,3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl,3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl,4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl,5-(1H-pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl,5,6,7,8-tetrahydroquinolin-3-yl, 5-phenylthiophen-2-yl,6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl,benzo[c][1,2,5]oxadiazol-4-yl, benzofuran-2-yl, benzofuran-5-yl,chroman-6-yl, chroman-7-yl, isoquinolin-5-yl, isoxazol-4-yl,pyridin-2-yl, pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl,quinolin-6-yl, quinolin-7-yl, and thiazol-4-yl. When referring to aheteroaryl group, it is understood that the terms thiophenyl,thiophen-2-yl, thiophen-3-yl, and the like, refer to the followingheteroaryl groups respectively:

The term “heterocyclyl” refers to a non-aromatic ring radical containing3 to 8 ring atoms, wherein one, two, or three of the ring atoms areheteroatoms selected from, for example: O, S, and N, wherein N isoptionally substituted with H, C₁-C₄ acyl, or C₁-C₄ alkyl. In someembodiments, “heterocyclyl” refers to a non-aromatic ring radicalcontaining 3 to 8 ring atoms, wherein one or two of the ring atoms areheteroatoms selected from, for example: O, S, and NH. Examples of aheterocyclyl group include aziridinyl, azetidinyl, piperidinyl,morpholinyl, oxetanyl, imidazolidinyl, piperazinyl, pyrrolidinyl,thiomorpholinyl, [1,4]oxazepanyl, azepanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothiopyranyl, and the like.

The term “hydroxyl” refers to the group —OH.

The term “C₁-C₆ alkylenehydroxyl” refers to a radical consisting of ahydroxyl group bonded to a C₁-C₆ alkylene radical, wherein hydroxyl andC₁-C₆ alkylene have the same definitions as described herein. Examplesinclude hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, and the like.

The term “oxo” refers to the diradical ═O.

The term “sulfamoyl” refers to the group —S(═O)₂NH₂.

COMPOUNDS OF THE INVENTION

One aspect of the present invention encompasses, inter alia, certain1-oxa-8-azaspiro[4.5]decan-3-yl-aminopropanyl-ether derivatives selectedfrom compounds of Formula (Ia) and pharmaceutically acceptable salts,solvates, and hydrates thereof:

wherein: R¹ (as well as Y and Z that are both related to R¹), X, W, R²,R^(3a), R^(3b), R^(3c) and R^(3d) all have the same definitions asdescribed herein, supra and infra. It is appreciated that certainfeatures of the invention, which are, for clarity, described in thecontext of separate embodiments, may also be provided in combination ina single embodiment. Conversely, various features of the invention,which are, for brevity, described in the context of a single embodiment,may also be provided separately or in any suitable subcombination. Allcombinations of the embodiments pertaining to the chemical groupsrepresented by the variables (e.g., R¹, X, W, R², R^(3a), R^(3b),R^(3c), and R^(3d); as well as R⁴, R^(5a), R^(5b), R^(5c), and R^(5d))contained within the generic chemical formulae described herein, forexample, Formulae (Ia), (Ia¹), (Ia²), (Ia³), (Ia⁴), (Ib), (Ic), (Ie),(Ig), (Ii), and the formulae disclosed in the figures, are specificallyembraced by the present invention just as if each and every combinationwas individually and explicitly recited, to the extent that suchcombinations embrace compounds that result in stable compounds (i.e.,compounds that can be isolated, characterized, and tested for biologicalactivity). In addition, all subcombinations of the chemical groupslisted in the embodiments describing such variables, as well as allsubcombinations of uses and medical indications described herein, arealso specifically embraced by the present invention just as if each andevery subcombination of chemical groups and subcombination of uses andmedical indications was individually and explicitly recited herein.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents, and the like.Likewise, “substituted with one or more substituents” refers to thesubstitution of a group substituted with one substituent up to the totalnumber of substituents physically allowed by the group. Further, when agroup is substituted with more than one group they can be identical orthey can be different.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers and the like. Tautomeric forms can be in equilibriumor sterically locked into one form by appropriate substitution. It isunderstood that the various tautomeric forms are within the scope of thecompounds of the present invention. One example relates to compoundscontaining the group described herein as 4-oxo-1,4-dihydroquinolin-3-yl,such as Compound 326. Even thou one tautomer is shown for a compound,such as shown in Table A, it is understood that the compound embracesall such tautomers;

below are two representative tautomers of4-oxo-1,4-dihydroquinolin-3-yl:

It is understood and appreciated that compounds of Formula (Ia) andformulae related thereto may have one or more chiral centers andtherefore can exist as enantiomers and/or diastereoisomers. Theinvention is understood to extend to and embrace all such enantiomers,diastereoisomers, and mixtures thereof, including but not limited toracemates.

In some embodiments, compounds of the present can have the followingdefined stereochemistry as shown in Formula (Ia¹):

wherein: R¹, X, W, R², R^(3a), R^(3b), R^(3c), and R^(3d), have the samedefinitions as described herein, supra and infra, and wherein the carbondesignated as C(3) of the oxa-azaspiro[4.5]decanyl group bonded to thenitrogen has the (R) stereochemistry and the carbon designated as C(2)of the propyl group bonded to the hydroxyl group has the (S)stereochemistry.

In some embodiments, compounds of the present can have the followingdefined stereochemistry as shown in Formula (Ia²):

wherein: R¹, X, W, R², R^(3a), R^(3b), R^(3c), and R^(3d), have the samedefinitions as described herein, supra and infra, and wherein the carbondesignated as C(3) of the oxa-azaspiro[4.5]decanyl group bonded to thenitrogen has the (R) stereochemistry and the carbon designated as C(2)of the propyl group bonded to the hydroxyl group has the (R)stereochemistry.

In some embodiments, compounds of the present can have the followingdefined stereochemistry as shown in Formula (Ia³):

wherein: R¹, X, W, R², R^(3a), R^(3b), R^(3c), and R^(3d), have the samedefinitions as described herein, supra and infra, and wherein the carbondesignated as C(3) of the oxa-azaspiro[4.5]decanyl group bonded to thenitrogen has the (S) stereochemistry and the carbon designated as C(2)of the propyl group bonded to the hydroxyl group has the (S)stereochemistry.

In some embodiments, compounds of the present can have the followingdefined stereochemistry as shown in Formula (Ia⁴):

wherein: R¹, X, W, R², R^(3a), R^(3b), R^(3c), and R^(3d), have the samedefinitions as described herein, supra and infra, and wherein the carbondesignated as C(3) of the oxa-azaspiro[4.5]decanyl group bonded to thenitrogen has the (S) stereochemistry and the carbon designated as C(2)of the propyl group bonded to the hydroxyl group has the (R)stereochemistry.

It is understood that any formulae described herein for which thestereochemistry is not specifically shown can be written to specificallyshow the stereochemistry as (R) and (S), (R) and (R), (S) and (S), or(S) and (R) for C(3) and C(2) respectively in a similar manner asFormulae (Ia¹), (Ia²), (Ia³), and (Ia⁴) shows the respectivestereochemistry for Formula (Ia), supra. Similarly, any formulaedescribed herein for which the stereochemistry is not specifically showncan alternatively be defined using the language as described forFormulae (Ia¹), (Ia²), (Ia³), and (Ia⁴), supra, to define thestereochemistry as (R) and (S), (R) and (R), (S) and (S), and (S) and(R) respectively.

Accordingly, in some embodiments, the stereochemistry for the C(3)carbon of the oxa-azaspiro[4.5]decanyl group bonded to the nitrogen is(R) and the stereochemistry for the C(2) carbon of the propyl groupbonded to the hydroxyl group is (S). In some embodiments, thestereochemistry for the C(3) carbon of the oxa-azaspiro[4.5]decanylgroup bonded to the nitrogen is (R) and the stereochemistry for the C(2)carbon of the propyl group bonded to the hydroxyl group is (R). In someembodiments, the stereochemistry for the C(3) carbon of theoxa-azaspiro[4.5]decanyl group bonded to the nitrogen is (S) and thestereochemistry for the C(2) carbon of the propyl group bonded to thehydroxyl group is (S). In some embodiments, the stereochemistry for theC(3) carbon of the oxa-azaspiro[4.5]decanyl group bonded to the nitrogenis (S) and the stereochemistry for the C(2) carbon of the propyl groupbonded to the hydroxyl group is (R).

It is understood that compounds of Formula (Ia) and formulae usedthroughout this disclosure represent all individual enantiomers andmixtures thereof, unless specifically stated or shown otherwise.

The X Group

In some embodiments, X is —SO₂—, —C(═O)—, or —CH₂C(═O)—.

In some embodiments, X is —SO₂—.

In some embodiments, X is —C(═O)—.

In some embodiments, X is —CH₂C(═O)—.

Ring W

In some embodiments, W is absent or C₁-C₃ alkylene.

In some embodiments, W is absent.

In some embodiments, W is C₁-C₃ alkylene.

In some embodiments, W is —CH₂—.

The Y and Z Groups

The Y and Z groups are related to certain substituents on R¹ where thesubstituent is selected from C₁-C₆ alkyl and C₃-C₇ cycloalkyl group andeach can be further optionally substituted with one or more substituentsselected from a group consisting of the following that contain eitherthe Y group or both the Y and Z groups: —Y—C₃-C₇-cycloalkyl and—Y—C₁-C₆-alkylene-Z.

In some embodiments, Y is independently selected from: —O—, —NH—, and—N—(C₁-C₄ alkyl)-.

In some embodiments, Z is independently selected from: hydroxyl, C₁-C₆alkoxy, amino, C₁-C₆ alkylamino, and C₂-C₆ dialkylamino.

It is understood that when more than one —Y—C₃-C₇-cycloalkyl and/or—Y—C₁-C₆-alkylene-Z group is present then Y and Z may be the same ordifferent.

In some embodiments, Y is —O—.

In some embodiments, Y is —NH—.

In some embodiments, Y is —N—(C₁-C₄ alkyl)-.

In some embodiments, Z is independently selected from: C₁-C₆ alkoxy,amino, and C₁-C₆ alkylamino.

In some embodiments, Z is hydroxyl.

In some embodiments, Z is C₁-C₆ alkoxy.

In some embodiments, Z is amino.

In some embodiments, Z is C₁-C₆ alkylamino.

In some embodiments, Z is C₂-C₆ dialkylamino.

The R¹ Group (Aryl and Heteroaryl)

In some embodiments, R¹ is aryl or heteroaryl, wherein each isoptionally substituted with one or more substituents selected from:C₁-C₆ alkoxy, C₁-C₆ alkyl, amino, cyano, C₃-C₇ cycloalkyl, C₁-C₆haloalkyl, halogen, hydroxyl, oxo, and sulfamoyl; and wherein said C₁-C₆alkyl and C₃-C₇ cycloalkyl are each optionally substituted with one ormore substituents selected from: amino, C₁-C₆ alkoxy, C₁-C₆alkylcarboxamide, —Y—C₃-C₇-cycloalkyl, —Y—C₁-C₆-alkylene-Z, C₁-C₆alkylamino, C₁-C₆ haloalkylamino, and heterocyclyl.

In some embodiments, R¹ is aryl or heteroaryl, wherein each isoptionally substituted with one or more substituents selected from:C₁-C₆ alkoxy, C₁-C₆ alkyl, amino, cyano, C₃-C₇ cycloalkyl, C₁-C₆haloalkyl, halogen, hydroxyl, oxo, and sulfamoyl; and wherein said C₁-C₆alkyl and C₃-C₇ cycloalkyl are each optionally substituted with one ormore substituents selected from: amino, C₁-C₆ alkoxy, C₁-C₆alkylcarboxamide, —NH—C₃-C₇-cycloalkyl, —NH—C₁-C₆-alkylene-NH₂,—NH—C₁-C₆-alkylene-O—C₁-C₆-alkyl, —NH—C₁-C₆-alkylene-NH—C₁-C₆-alkyl,C₁-C₆ alkylamino, C₁-C₆ haloalkylamino, and heterocyclyl.

In some embodiments, R¹ is selected from: (1H-pyrazolyl)phenyl,(1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl,1,2,3,4-tetrahydropyrido[3,2-b]pyrazinyl, 1,2-dihydroquinolinyl,1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl,1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl,2,3-dihydro-1H-imidazo[4,5-b]pyridinyl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,3,4-dihydro-2H-pyrano[2,3-b]pyridinyl,3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl,(phenyl)pyridinyl, 5,6,7,8-tetrahydronaphthalenyl,5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl,benzo[c][1,2,5]oxadiazolyl, benzofuranyl, biphenyl, chromanyl,isoquinolinyl, isoxazolyl, naphthalenyl, phenyl, phenylthiophenyl,pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl, and thiazolyl; whereineach is optionally substituted with one or more substituents selectedfrom: 2-methylpropan-2-yl, amino, bromo, chloro, cyclopropyl, ethoxy,ethyl, fluoro, hydroxy, isopropoxy, methoxy, methyl, oxo, propan-2-yl,propan-1-yl, sulfamoyl, and trifluoromethyl; and wherein said2-methylpropan-2-yl, cyclopropyl, ethyl, methyl, and propan-2-yl areeach optionally substituted with one or more substituents selected from:2,2,2-trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino,3-aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino,cyclobutylamino, ethylamino, isobutylamino, isopropylamino, methoxy,methylamino, morpholino, propylamino, tert-butylamino, andtert-pentylamino.

In some embodiments, R¹ is selected from: (1H-pyrazolyl)phenyl,(1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl,1,2,3,4-tetrahydropyrido[3,2-b]pyrazinyl, 1,2-dihydroquinolinyl,1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl,1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl,2,3-dihydro-1H-imidazo[4,5-b]pyridinyl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,3,4-dihydro-2H-pyrano[2,3-b]pyridinyl,3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl,(phenyl)pyridinyl, 5,6,7,8-tetrahydronaphthalenyl,5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl,benzo[c][1,2,5]oxadiazolyl, benzofuranyl, biphenyl, chromanyl,isoquinolinyl, isoxazolyl, naphthalenyl, phenyl, phenylthiophenyl,pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl, and thiazolyl; whereineach is optionally substituted with one or more substituents selectedfrom: (2,2,2-trifluoroethylamino)methyl, (2-aminoethylamino)methyl,(2-methoxyethylamino)methyl, (3-aminopropylamino)methyl,(butylamino)methyl, (cyclobutylamino)methyl, (ethylamino)methyl,(isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl,(propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl,1-amino-2-methylpropan-2-yl, 1-aminocyclopropyl, 2-acetamidoethyl,2-aminoethyl, 2-aminopropan-2-yl, 2-methoxyethyl, amino, aminomethyl,azetidin-1-ylmethyl, bromo, chloro, cyano, cyclopropyl, ethoxy, ethyl,fluoro, hydroxy, isopropoxy, methoxy, methyl, morpholinomethyl, oxo,propan-1-yl, sulfamoyl, and trifluoromethyl.

In some embodiments, R¹ is selected from:1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl, 1,2-dihydroquinolin-6-yl,1,4-dihydroquinolin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl,1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl,1H-pyrazol-4-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl,1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 2,3-dihydrobenzofuran-5-yl,3-(1H-pyrazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl,3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl,3-(pyrimidin-5-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl,3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl,3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl,3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl,4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl,5-(1H-pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl,5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl,5-phenylthiophen-2-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl,benzo[c][1,2,5]oxadiazol-4-yl, benzofuran-2-yl, benzofuran-5-yl,biphenyl-3-yl, biphenyl-4-yl, chroman-6-yl, chroman-7-yl,isoquinolin-5-yl, isoxazol-4-yl, naphthalen-2-yl, phenyl, pyridin-2-yl,pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl,quinolin-6-yl, quinolin-7-yl, and thiazol-4-yl; wherein each isoptionally substituted with one or more substituents selected from:(2,2,2-trifluoroethylamino)methyl, (2-aminoethylamino)methyl,(2-methoxyethylamino)methyl, (3-aminopropylamino)methyl,(butylamino)methyl, (cyclobutylamino)methyl, (ethylamino)methyl,(isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl,(propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl,1-amino-2-methylpropan-2-yl, 1-aminocyclopropyl, 2-acetamidoethyl,2-aminoethyl, 2-aminopropan-2-yl, 2-methoxyethyl, amino, aminomethyl,azetidin-1-ylmethyl, bromo, chloro, cyano, cyclopropyl, ethoxy, ethyl,fluoro, hydroxy, isopropoxy, methoxy, methyl, morpholinomethyl, oxo,propan-1-yl, sulfamoyl, and trifluoromethyl.

In some embodiments, R¹ is selected from:(R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,(S)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl,1,4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl,1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-ethoxynaphthalen-2-yl,1-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-5-methyl-1H-pyrazol-4-yl,1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-6-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-8-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl, 1H-indol-2-yl, 1H-indol-3-yl,1H-indol-5-yl, 1H-indol-6-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl,1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl,1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-methyl-4-oxo-1,4-dihydroquinolin-3-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,2,3-dihydrobenzofuran-5-yl, 2-aminothiazol-4-yl,2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl,3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl,3-(1-ethyl-1H-pyrazol-4-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl,3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1H-pyrazol-4-yl)phenyl,3-(2-methylpyridin-4-yl)phenyl, 3-(3-fluoropyridin-2-yl)phenyl,3-(4-methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2-yl)phenyl,3-(6-(trifluoromethyl)pyridin-2-yl)phenyl,3-(6-aminopyridin-3-yl)phenyl, 3-(6-fluoropyridin-2-yl)phenyl,3-(6-methylpyridin-2-yl)phenyl, 3-(pyridin-2-yl)phenyl,3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl,3-(pyrimidin-5-yl)phenyl, 3-(trifluoromethyl)phenyl,3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl, 3,5-dimethylisoxazol-4-yl,3-bromo-2-methylphenyl, 3-bromo-4-methoxyphenyl, 3-bromophenyl,3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3-methoxyphenyl,3-methyl-3H-imidazo[4,5-b]pyridin-5-yl,3-methyl-3H-imidazo[4,5-b]pyridin-6-yl,3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,4′-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl,4′-((2-aminoethylamino)methyl)biphenyl-3-yl,4′-((2-methoxyethylamino)methyl)biphenyl-3-yl,4′-((3-aminopropylamino)methyl)biphenyl-3-yl,4′-((butylamino)methyl)biphenyl-3-yl,4′-((cyclobutylamino)methyl)biphenyl-3-yl,4′-((ethylamino)methyl)biphenyl-3-yl,4′-((isobutylamino)methyl)biphenyl-3-yl,4′-((isopropylamino)methyl)biphenyl-3-yl,4′-((methylamino)methyl)biphenyl-3-yl,4′-((propylamino)methyl)biphenyl-3-yl,4′-((tert-butylamino)methyl)biphenyl-3-yl,4′-((tert-pentylamino)methyl)biphenyl-3-yl,4′-(1-amino-2-methylpropan-2-yl)-4-ethoxybiphenyl-3-yl,4′-(1-amino-2-methylpropan-2-yl)biphenyl-3-yl,4′-(1-aminocyclopropyl)-2-methylbiphenyl-3-yl,4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-yl,4′-(1-aminocyclopropyl)-6-fluorobiphenyl-3-yl,4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl,4′-(1-aminocyclopropyl)biphenyl-3-yl,4′-(2-acetamidoethyl)-4-ethoxy-biphenyl-3-yl,4′-(2-acetamidoethyl)-biphenyl-3-yl,4′-(2-aminoethyl)-4-ethoxybiphenyl-3-yl,4′-(2-aminoethyl)-6-methoxybiphenyl-3-yl,4′-(2-aminoethyl)biphenyl-3-yl,4′-(2-aminopropan-2-yl)-4-ethoxybiphenyl-3-yl,4′-(aminomethyl)-2-methoxybiphenyl-3-yl,4′-(aminomethyl)-2-methylbiphenyl-3-yl,4′-(aminomethyl)-3′-fluorobiphenyl-3-yl,4′-(aminomethyl)-4-ethoxy-3′-fluorobiphenyl-3-yl,4′-(aminomethyl)-4-ethoxybiphenyl-3-yl,4′-(aminomethyl)-4-fluorobiphenyl-3-yl,4′-(aminomethyl)-4-isopropoxybiphenyl-3-yl,4′-(aminomethyl)-5-methoxybiphenyl-3-yl,4′-(aminomethyl)-6-ethoxybiphenyl-3-yl,4′-(aminomethyl)-6-fluorobiphenyl-3-yl,4′-(aminomethyl)-6-methoxybiphenyl-3-yl, 4′-(aminomethyl)biphenyl-3-yl,4′-(aminomethyl)biphenyl-4-yl, 4′-(azetidin-1-ylmethyl)biphenyl-3-yl,4′-(morpholinomethyl)biphenyl-3-yl, 4-(pyridin-2-yl)phenyl,4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl,4′-(sulfamoyl)biphenyl-3-yl, 4-bromo-3-methylphenyl,4-ethoxy-4′-((isopropylamino)methyl)biphenyl-3-yl,4-hydroxy-6-methylquinolin-3-yl, 4-hydroxy-7-methylquinolin-3-yl,4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl,4-methoxyquinolin-3-yl, 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl,4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl,4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl,4′-methylbiphenyl-3-yl, 4-oxo-1,4-dihydroquinolin-3-yl,5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl,5-(4-(aminomethyl)phenyl)pyridin-3-yl,5,6,7,8-tetrahydronaphthalen-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl,5-bromo-6-chloropyridin-3-yl, 5-bromopyridin-3-yl,5-chloronaphthalen-2-yl,5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 5-phenylthiophen-2-yl,6-chloronaphthalen-2-yl, 6-fluoro-4-hydroxyquinolin-3-yl,7-chlorobenzo[c][1,2,5]oxadiazol-4-yl, 7-fluoro-4-hydroxyquinolin-3-yl,8-fluoro-4-hydroxyquinolin-3-yl, benzofuran-2-yl, benzofuran-5-yl,chroman-6-yl, chroman-7-yl, isoquinolin-5-yl, m-tolyl, naphthalen-2-yl,phenyl, pyridin-2-yl, pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl,quinolin-3-yl, quinolin-6-yl, and quinolin-7-yl.

In some embodiments, R¹ is(R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R¹ is(S)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R¹ is1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R¹ is1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl.

In some embodiments, R¹ is1,4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl.

In some embodiments, R¹ is1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R¹ is1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R¹ is 1-ethoxynaphthalen-2-yl.

In some embodiments, R¹ is1-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R¹ is 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R¹ is 1-ethyl-5-methyl-1H-pyrazol-4-yl.

In some embodiments, R¹ is1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R¹ is1-ethyl-6-methyl-4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R¹ is1-ethyl-7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R¹ is1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R¹ is1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R¹ is1-ethyl-8-methyl-4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R¹ is 1H-benzo[d]imidazol-5-yl.

In some embodiments, R¹ is 1H-indazol-5-yl.

In some embodiments, R¹ is 1H-indol-2-yl.

In some embodiments, R¹ is 1H-indol-3-yl.

In some embodiments, R¹ is 1H-indol-5-yl.

In some embodiments, R¹ is 1H-indol-6-yl.

In some embodiments, R¹ is 1H-pyrazolo[4,3-b]pyridin-6-yl.

In some embodiments, R¹ is 1H-pyrrolo[2,3-b]pyridin-3-yl.

In some embodiments, R¹ is 1H-pyrrolo[3,2-b]pyridin-6-yl.

In some embodiments, R¹ is1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R¹ is 1-methyl-4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R¹ is 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl.

In some embodiments, R¹ is 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl.

In some embodiments, R¹ is 2,3-dihydrobenzofuran-5-yl.

In some embodiments, R¹ is 2-aminothiazol-4-yl.

In some embodiments, R¹ is2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl.

In some embodiments, R¹ is2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl.

In some embodiments, R¹ is 3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl.

In some embodiments, R¹ is 3-(1-ethyl-1H-pyrazol-4-yl)phenyl.

In some embodiments, R¹ is 3-(1H-pyrazol-4-yl)phenyl.

In some embodiments, R¹ is 3-(1-methyl-1H-pyrazol-4-yl)phenyl.

In some embodiments, R¹ is 3-(1-propyl-1H-pyrazol-4-yl)phenyl.

In some embodiments, R¹ is 3-(2-methylpyridin-4-yl)phenyl.

In some embodiments, R¹ is 3-(3-fluoropyridin-2-yl)phenyl.

In some embodiments, R¹ is 3-(4-methylpyridin-2-yl)phenyl.

In some embodiments, R¹ is 3-(5-methylpyridin-2-yl)phenyl.

In some embodiments, R¹ is 3-(6-(trifluoromethyl)pyridin-2-yl)phenyl.

In some embodiments, R¹ is 3-(6-aminopyridin-3-yl)phenyl.

In some embodiments, R¹ is 3-(6-fluoropyridin-2-yl)phenyl.

In some embodiments, R¹ is 3-(6-methylpyridin-2-yl)phenyl.

In some embodiments, R¹ is 3-(pyridin-2-yl)phenyl.

In some embodiments, R¹ is 3-(pyridin-3-yl)phenyl.

In some embodiments, R¹ is 3-(pyridin-4-yl)phenyl.

In some embodiments, R¹ is 3-(pyrimidin-5-yl)phenyl.

In some embodiments, R¹ is 3-(trifluoromethyl)phenyl.

In some embodiments, R¹ is 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl.

In some embodiments, R¹ is 3,5-dimethylisoxazol-4-yl.

In some embodiments, R¹ is 3-bromo-2-methylphenyl.

In some embodiments, R¹ is 3-bromo-4-methoxyphenyl.

In some embodiments, R¹ is 3-bromophenyl.

In some embodiments, R¹ is 3-chlorophenyl.

In some embodiments, R¹ is 3-cyanophenyl.

In some embodiments, R¹ is 3-fluorophenyl.

In some embodiments, R¹ is 3-methoxyphenyl.

In some embodiments, R¹ is 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl.

In some embodiments, R¹ is 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl.

In some embodiments, R¹ is3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl.

In some embodiments, R¹ is4′-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-((2-aminoethylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is4′-((2-methoxyethylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-((3-aminopropylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-((butylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-((cyclobutylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-((ethylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-((isobutylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-((isopropylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-((methylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-((propylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-((tert-butylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-((tert-pentylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is4′-(1-amino-2-methylpropan-2-yl)-4-ethoxybiphenyl-3-yl.

In some embodiments, R¹ is4′-(1-amino-2-methylpropan-2-yl)biphenyl-3-yl.

In some embodiments, R¹ is4′-(1-aminocyclopropyl)-2-methylbiphenyl-3-yl.

In some embodiments, R¹ is4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-yl.

In some embodiments, R¹ is 4′(1-aminocyclopropyl)-6-fluorobiphenyl-3-yl.

In some embodiments, R¹ is4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl.

In some embodiments, R¹ is 4′-(1-aminocyclopropyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-(2-acetamidoethyl)-4-ethoxy-biphenyl-3-yl.

In some embodiments, R¹ is 4′-(2-acetamidoethyl)-biphenyl-3-yl.

In some embodiments, R¹ is 4′-(2-aminoethyl)-4-ethoxybiphenyl-3-yl.

In some embodiments, R¹ is 4′-(2-aminoethyl)-6-methoxybiphenyl-3-yl.

In some embodiments, R¹ is 4′-(2-aminoethyl)biphenyl-3-yl.

In some embodiments, R¹ is4′-(2-aminopropan-2-yl)-4-ethoxybiphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)-2-methoxybiphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)-2-methylbiphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)-3′-fluorobiphenyl-3-yl.

In some embodiments, R¹ is4′-(aminomethyl)-4-ethoxy-3′-fluorobiphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)-4-ethoxybiphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)-4-fluorobiphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)-4-isopropoxybiphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)-5-methoxybiphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)-6-ethoxybiphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)-6-fluorobiphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)-6-methoxybiphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-(aminomethyl)biphenyl-4-yl.

In some embodiments, R¹ is 4′-(azetidin-1-ylmethyl)biphenyl-3-yl.

In some embodiments, R¹ is 4′-(morpholinomethyl)biphenyl-3-yl.

In some embodiments, R¹ is 4-(pyridin-2-yl)phenyl.

In some embodiments, R¹ is 4-(pyridin-3-yl)phenyl.

In some embodiments, R¹ is 4-(pyridin-4-yl)phenyl.

In some embodiments, R¹ is 4′-(sulfamoyl)biphenyl-3-yl.

In some embodiments, R¹ is 4-bromo-3-methylphenyl.

In some embodiments, R¹ is4-ethoxy-4′-((isopropylamino)methyl)biphenyl-3-yl.

In some embodiments, R¹ is 4-hydroxy-6-methylquinolin-3-yl.

In some embodiments, R¹ is 4-hydroxy-7-methylquinolin-3-yl.

In some embodiments, R¹ is 4-hydroxy-8-methylquinolin-3-yl.

In some embodiments, R¹ is 4-hydroxyquinolin-3-yl.

In some embodiments, R¹ is 4-methoxyquinolin-3-yl.

In some embodiments, R¹ is 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl.

In some embodiments, R¹ is4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl.

In some embodiments, R¹ is4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl.

In some embodiments, R¹ is4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl.

In some embodiments, R¹ is 4′-methylbiphenyl-3-yl.

In some embodiments, R¹ is 4-oxo-1,4-dihydroquinolin-3-yl.

In some embodiments, R¹ is 5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl.

In some embodiments, R¹ is 5-(4-(aminomethyl)phenyl)pyridin-3-yl.

In some embodiments, R¹ is 5,6,7,8-tetrahydronaphthalen-2-yl.

In some embodiments, R¹ is 5,6,7,8-tetrahydroquinolin-3-yl.

In some embodiments, R¹ is 5-bromo-6-chloropyridin-3-yl.

In some embodiments, R¹ is 5-bromopyridin-3-yl.

In some embodiments, R¹ is 5-chloronaphthalen-2-yl.

In some embodiments, R¹ is5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl.

In some embodiments, R¹ is 5-phenylthiophen-2-yl.

In some embodiments, R¹ is 6-chloronaphthalen-2-yl.

In some embodiments, R¹ is 6-fluoro-4-hydroxyquinolin-3-yl.

In some embodiments, R¹ is 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl.

In some embodiments, R¹ is 7-fluoro-4-hydroxyquinolin-3-yl.

In some embodiments, R¹ is 8-fluoro-4-hydroxyquinolin-3-yl.

In some embodiments, R¹ is benzofuran-2-yl.

In some embodiments, R¹ is benzofuran-5-yl.

In some embodiments, R¹ is chroman-6-yl.

In some embodiments, R¹ is chroman-7-yl.

In some embodiments, R¹ is isoquinolin-5-yl.

In some embodiments, R¹ is m-tolyl.

In some embodiments, R¹ is naphthalen-2-yl.

In some embodiments, R¹ is phenyl.

In some embodiments, R¹ is pyridin-2-yl.

In some embodiments, R¹ is pyridin-3-yl.

In some embodiments, R¹ is pyrrolo[1,2-a]pyrimidin-3-yl.

In some embodiments, R¹ is quinolin-3-yl.

In some embodiments, R¹ is quinolin-6-yl.

In some embodiments, R¹ is and quinolin-7-yl.

The R¹ Group (Aryl)

In some embodiments, R¹ is aryl, wherein each is optionally substitutedwith one or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,amino, cyano, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen, hydroxyl, oxo,and sulfamoyl; and wherein said C₁-C₆ alkyl and C₃-C₇ cycloalkyl areeach optionally substituted with one or more substituents selected from:amino, C₁-C₆ alkoxy, C₁-C₆ alkylcarboxamide, —Y—C₃-C₇-cycloalkyl,—Y—C₁-C₆-alkylene-Z, C₁-C₆ alkylamino, C₁-C₆ haloalkylamino, andheterocyclyl.

In some embodiments, R¹ is aryl optionally substituted with one or moresubstituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, cyano, C₃-C₇cycloalkyl, C₁-C₆ haloalkyl, halogen, and sulfamoyl; and wherein saidC₁-C₆ alkyl and C₃-C₇ cycloalkyl are each optionally substituted withone or more substituents selected from: amino, C₁-C₆ alkylcarboxamide,—NH—C₃-C₇-cycloalkyl, —NH—C₁-C₆-alkylene-NH₂,—NH—C₁-C₆-alkylene-O—C₁-C₆-alkyl, C₁-C₆ alkylamino, C₁-C₆haloalkylamino, and heterocyclyl.

In some embodiments, R¹ is selected from:5,6,7,8-tetrahydronaphthalenyl, biphenyl, naphthalenyl, and phenyl;wherein each is optionally substituted with one or more substituentsselected from: 2-methylpropan-2-yl, bromo, chloro, cyano, cyclopropyl,ethoxy, ethyl, fluoro, isopropoxy, methoxy, methyl, propan-2-yl,sulfamoyl, and trifluoromethyl; and wherein said 2-methylpropan-2-yl,cyclopropyl, ethyl, methyl, and propan-2-yl are each optionallysubstituted with one or more substituents selected from:2,2,2-trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino,3-aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino,cyclobutylamino, ethylamino, isobutylamino, isopropylamino, methylamino,morpholino, propylamino, tert-butylamino, and tert-pentylamino.

In some embodiments, R¹ is selected from:5,6,7,8-tetrahydronaphthalenyl, biphenyl, naphthalenyl, and phenyl;wherein each is optionally substituted with one or more substituentsselected from: (2,2,2-trifluoroethylamino)methyl,(2-aminoethylamino)methyl, (2-methoxyethylamino)methyl,(3-aminopropylamino)methyl, (butylamino)methyl, (cyclobutylamino)methyl,(ethylamino)methyl, (isobutylamino)methyl, (isopropylamino)methyl,(methylamino)methyl, (propylamino)methyl, (tert-butylamino)methyl,(tert-pentylamino)methyl, 1-amino-2-methylpropan-2-yl,1-aminocyclopropyl, 2-acetamidoethyl, 2-aminoethyl, 2-aminopropan-2-yl,aminomethyl, azetidin-1-ylmethyl, bromo, chloro, cyano, ethoxy, fluoro,isopropoxy, methoxy, methyl, morpholinomethyl, sulfamoyl, andtrifluoromethyl.

In some embodiments, R¹ is selected from:5,6,7,8-tetrahydronaphthalen-2-yl, biphenyl-3-yl, biphenyl-4-yl,naphthalen-2-yl, and phenyl; wherein each is optionally substituted withone or more substituents selected from:(2,2,2-trifluoroethylamino)methyl, (2-aminoethylamino)methyl,(2-methoxyethylamino)methyl, (3-aminopropylamino)methyl,(butylamino)methyl, (cyclobutylamino)methyl, (ethylamino)methyl,(isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl,(propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl,1-amino-2-methylpropan-2-yl, 1-aminocyclopropyl, 2-acetamidoethyl,2-aminoethyl, 2-aminopropan-2-yl, aminomethyl, azetidin-1-ylmethyl,bromo, chloro, cyano, ethoxy, fluoro, isopropoxy, methoxy, methyl,morpholinomethyl, sulfamoyl, and trifluoromethyl.

In some embodiments, R¹ is selected from: 1-ethoxynaphthalen-2-yl,3-(trifluoromethyl)phenyl, 3-bromo-2-methylphenyl,3-bromo-4-methoxyphenyl, 3-bromophenyl, 3-chlorophenyl, 3-cyanophenyl,3-fluorophenyl, 3-methoxyphenyl,4′-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl,4′-((2-aminoethylamino)methyl)biphenyl-3-yl,4′-((2-methoxyethylamino)methyl)biphenyl-3-yl,4′-((3-aminopropylamino)methyl)biphenyl-3-yl,4′-((butylamino)methyl)biphenyl-3-yl,4′-((cyclobutylamino)methyl)biphenyl-3-yl,4′-((ethylamino)methyl)biphenyl-3-yl,4′-((isobutylamino)methyl)biphenyl-3-yl,4′-((isopropylamino)methyl)biphenyl-3-yl,4′-((methylamino)methyl)biphenyl-3-yl,4′-((propylamino)methyl)biphenyl-3-yl,4′-((tert-butylamino)methyl)biphenyl-3-yl,4′-((tert-pentylamino)methyl)biphenyl-3-yl,4′-(1-amino-2-methylpropan-2-yl)-4-ethoxybiphenyl-3-yl,4′-(1-amino-2-methylpropan-2-yl)biphenyl-3-yl,4′-(1-aminocyclopropyl)-2-methylbiphenyl-3-yl,4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-yl,4′-(1-aminocyclopropyl)-6-fluorobiphenyl-3-yl,4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl,4′-(1-aminocyclopropyl)biphenyl-3-yl,4′-(2-acetamidoethyl)-4-ethoxy-biphenyl-3-yl,4′-(2-acetamidoethyl)-biphenyl-3-yl,4′-(2-aminoethyl)-4-ethoxybiphenyl-3-yl,4′-(2-aminoethyl)-6-methoxybiphenyl-3-yl,4′-(2-aminoethyl)biphenyl-3-yl,4′-(2-aminopropan-2-yl)-4-ethoxybiphenyl-3-yl,4′-(aminomethyl)-2-methoxybiphenyl-3-yl,4′-(aminomethyl)-2-methylbiphenyl-3-yl,4′-(aminomethyl)-3′-fluorobiphenyl-3-yl,4′-(aminomethyl)-4-ethoxy-3′-fluorobiphenyl-3-yl,4′-(aminomethyl)-4-ethoxybiphenyl-3-yl,4′-(aminomethyl)-4-fluorobiphenyl-3-yl,4′-(aminomethyl)-4-isopropoxybiphenyl-3-yl,4′-(aminomethyl)-5-methoxybiphenyl-3-yl,4′-(aminomethyl)-6-ethoxybiphenyl-3-yl,4′-(aminomethyl)-6-fluorobiphenyl-3-yl,4′-(aminomethyl)-6-methoxybiphenyl-3-yl, 4′-(aminomethyl)biphenyl-3-yl,4′-(aminomethyl)biphenyl-4-yl, 4′-(azetidin-1-ylmethyl)biphenyl-3-yl,4′-(morpholinomethyl)biphenyl-3-yl, 4′-(sulfamoyl)biphenyl-3-yl,4-bromo-3-methylphenyl,4-ethoxy-4′-((isopropylamino)methyl)biphenyl-3-yl,4′-methylbiphenyl-3-yl, 5,6,7,8-tetrahydronaphthalen-2-yl,5-chloronaphthalen-2-yl, 6-chloronaphthalen-2-yl, m-tolyl,naphthalen-2-yl, and phenyl.

The R¹ Group (Heteroaryl)

In some embodiments, R¹ is heteroaryl, wherein each is optionallysubstituted with one or more substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkyl, amino, cyano, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen,hydroxyl, oxo, and sulfamoyl; and wherein said C₁-C₆ alkyl and C₃-C₇cycloalkyl are each optionally substituted with one or more substituentsselected from: amino, C₁-C₆ alkoxy, C₁-C₆ alkylcarboxamide,—Y—C₃-C₇-cycloalkyl, —Y—C₁-C₆-alkylene-Z, C₁-C₆ alkylamino, C₁-C₆haloalkylamino, and heterocyclyl.

In some embodiments, R¹ is heteroaryl optionally substituted with one ormore substituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl, amino, C₃-C₇cycloalkyl, C₁-C₆ haloalkyl, halogen, hydroxyl, and oxo; and whereinsaid C₁-C₆ alkyl is optionally substituted with one or more substituentsselected from: amino and C₁-C₆ alkoxy.

In some embodiments, R¹ is selected from: (1H-pyrazolyl)phenyl,(1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl,1,2,3,4-tetrahydropyrido[3,2-b]pyrazinyl, 1,2-dihydroquinolinyl,1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl,1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl,2,3-dihydro-1H-imidazo[4,5-b]pyridinyl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,3,4-dihydro-2H-pyrano[2,3-b]pyridinyl,3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl,(phenyl)pyridinyl, 5,6,7,8-tetrahydroquinolinyl,6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl,benzofuranyl, chromanyl, isoquinolinyl, isoxazolyl, phenylthiophenyl,pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl, and thiazolyl; whereineach is optionally substituted with one or more substituents selectedfrom: amino, bromo, chloro, cyclopropyl, ethyl, fluoro, hydroxy,methoxy, methyl, oxo, propan-1-yl, and trifluoromethyl; and wherein saidethyl and methyl are each optionally substituted with one or moresubstituents selected from: amino and methoxy.

In some embodiments, R¹ is selected from: (1H-pyrazolyl)phenyl,(1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl,1,2,3,4-tetrahydropyrido[3,2-b]pyrazinyl, 1,2-dihydroquinolinyl,1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl,1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl,2,3-dihydro-1H-imidazo[4,5-b]pyridinyl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,3,4-dihydro-2H-pyrano[2,3-b]pyridinyl,3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl,(phenyl)pyridinyl, 5,6,7,8-tetrahydroquinolinyl,6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl,benzofuranyl, chromanyl, isoquinolinyl, isoxazolyl, phenylthiophenyl,pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl, and thiazolyl; whereineach is optionally substituted with one or more substituents selectedfrom: 2-methoxyethyl, amino, aminomethyl, bromo, chloro, cyclopropyl,ethyl, fluoro, hydroxy, methoxy, methyl, oxo, propan-1-yl, andtrifluoromethyl.

In some embodiments, R¹ is selected from:1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl, 1,2-dihydroquinolin-6-yl,1,4-dihydroquinolin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl,1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl,1H-pyrazol-4-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl,1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 2,3-dihydrobenzofuran-5-yl,3-(1H-pyrazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl,3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl,3-(pyrimidin-5-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl,3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl,3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl,3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl,4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl,5-(1H-pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl,5,6,7,8-tetrahydroquinolin-3-yl, 5-phenylthiophen-2-yl,6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl,benzo[c][1,2,5]oxadiazol-4-yl, benzofuran-2-yl, benzofuran-5-yl,chroman-6-yl, chroman-7-yl, isoquinolin-5-yl, isoxazol-4-yl,pyridin-2-yl, pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl,quinolin-6-yl, quinolin-7-yl, and thiazol-4-yl; wherein each isoptionally substituted with one or more substituents selected from:2-methoxyethyl, amino, aminomethyl, bromo, chloro, cyclopropyl, ethyl,fluoro, hydroxy, methoxy, methyl, oxo, propan-1-yl, and trifluoromethyl.

In some embodiments, R¹ is selected from:(R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,(S)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl,1,4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl,1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-5-methyl-1H-pyrazol-4-yl,1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-6-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-8-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl, 1H-indol-2-yl, 1H-indol-3-yl,1H-indol-5-yl, 1H-indol-6-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl,1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl,1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-methyl-4-oxo-1,4-dihydroquinolin-3-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,2,3-dihydrobenzofuran-5-yl, 2-aminothiazol-4-yl,2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl,3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl,3-(1-ethyl-1H-pyrazol-4-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl,3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1H-pyrazol-4-yl)phenyl,3-(2-methylpyridin-4-yl)phenyl, 3-(3-fluoropyridin-2-yl)phenyl,3-(4-methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2-yl)phenyl,3-(6-(trifluoromethyl)pyridin-2-yl)phenyl,3-(6-aminopyridin-3-yl)phenyl, 3-(6-fluoropyridin-2-yl)phenyl,3-(6-methylpyridin-2-yl)phenyl, 3-(pyridin-2-yl)phenyl,3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl,3-(pyrimidin-5-yl)phenyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl,3,5-dimethylisoxazol-4-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl,3-methyl-3H-imidazo[4,5-b]pyridin-6-yl,3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-(pyridin-2-yl)phenyl,4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl,4-hydroxy-6-methylquinolin-3-yl, 4-hydroxy-7-methylquinolin-3-yl,4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl,4-methoxyquinolin-3-yl, 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl,4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl,4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl,4-oxo-1,4-dihydroquinolin-3-yl,5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl,5-(4-(aminomethyl)phenyl)pyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl,5-bromo-6-chloropyridin-3-yl, 5-bromopyridin-3-yl,5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 5-phenylthiophen-2-yl,6-fluoro-4-hydroxyquinolin-3-yl, 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl,7-fluoro-4-hydroxyquinolin-3-yl, 8-fluoro-4-hydroxyquinolin-3-yl,benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, chroman-7-yl,isoquinolin-5-yl, pyridin-2-yl, pyridin-3-yl,pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinolin-6-yl, andquinolin-7-yl.

The R² Group

In some embodiments, R² is selected from: C₂-C₆ alkenyl, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, heterocyclyl, and C₁-C₆haloalkyl; each optionallysubstituted with one or more substituents selected from: C₁-C₆ alkoxy,C₁-C₆ alkylenehydroxyl, amino, aryl, C₃-C₇ cycloalkyl, cyano, C₃-C₇halocycloalkyl, hydroxyl, and oxo.

In some embodiments, R² is selected from: 1,1-difluoroethyl,1-fluoroethyl, 2-methylpropan-2-yl, 3,3,3-trifluoropropyl,4,4,4-trifluorobutyl, azetidin-3-yl, cyclobutyl, cyclopentyl,cyclopropyl, ethyl, fluoromethyl, isobutyl, isopentyl, isopropyl,methyl, oxetan-3-yl, propan-1-yl, sec-butyl, and vinyl; each optionallysubstituted with one or more substituents selected from:2,2-difluorocyclopropyl, amino, cyano, cyclobutyl, cyclohexyl,cyclopropyl, ethoxy, hydroxy, hydroxymethyl, methoxy, oxo, and phenyl.

In some embodiments, R² is selected from:(2,2-difluorocyclopropyl)methyl, 1-(hydroxymethyl)cyclobutyl,1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl,1-amino-2-methyl-1-oxopropan-2-yl, 1-ethoxy-2-methyl-1-oxopropan-2-yl,1-fluoroethyl, 1-hydroxy-2-methylpropan-2-yl, 2-amino-2-oxoethyl,2-aminoethyl, 2-hydroxyethyl, 3,3,3-trifluoropropyl,3-amino-3-oxopropyl, 3-hydroxycyclobutyl, 3-hydroxypropyl,3-methoxypropyl, 4,4,4-trifluorobutyl, azetidin-3-yl, benzyl,carboxymethyl, cyanomethyl, cyclobutyl, cyclobutylmethyl,cyclohexylmethyl, cyclopentyl, cyclopropyl, cyclopropylmethyl, ethyl,fluoromethyl, isobutyl, isopentyl, isopropyl, methoxymethyl, methyl,oxetan-3-yl, propan-1-yl, sec-butyl, and vinyl.

In some embodiments, R² is selected from: 1-(hydroxymethyl)cyclobutyl,1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl,1-fluoroethyl, 1-hydroxy-2-methylpropan-2-yl, 2-amino-2-oxoethyl,2-hydroxyethyl, 3-amino-3-oxopropyl, 3-hydroxypropyl, 3-methoxypropyl,cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl, isobutyl, isopropyl,methoxymethyl, methyl, and propan-1-yl.

In some embodiments, R² is (2,2-difluorocyclopropyl)methyl.

In some embodiments, R² is 1-(hydroxymethyl)cyclobutyl.

In some embodiments, R² is 1-(hydroxymethyl)cyclopropyl.

In some embodiments, R² is 1,1-difluoro-2-hydroxyethyl.

In some embodiments, R² is 1-amino-2-methyl-1-oxopropan-2-yl.

In some embodiments, R² is 1-ethoxy-2-methyl-1-oxopropan-2-yl.

In some embodiments, R² is 1-fluoroethyl.

In some embodiments, R² is 1-hydroxy-2-methylpropan-2-yl.

In some embodiments, R² is 2-amino-2-oxoethyl.

In some embodiments, R² is 2-aminoethyl.

In some embodiments, R² is 2-hydroxyethyl.

In some embodiments, R² is 3,3,3-trifluoropropyl.

In some embodiments, R² is 3-amino-3-oxopropyl.

In some embodiments, R² is 3-hydroxycyclobutyl.

In some embodiments, R² is 3-hydroxypropyl.

In some embodiments, R² is 3-methoxypropyl.

In some embodiments, R² is 4,4,4-trifluorobutyl.

In some embodiments, R² is azetidin-3-yl.

In some embodiments, R² is benzyl.

In some embodiments, R² is carboxymethyl.

In some embodiments, R² is cyanomethyl.

In some embodiments, R² is cyclobutyl.

In some embodiments, R² is cyclobutylmethyl.

In some embodiments, R² is cyclohexylmethyl.

In some embodiments, R² is cyclopentyl.

In some embodiments, R² is cyclopropyl.

In some embodiments, R² is cyclopropylmethyl.

In some embodiments, R² is ethyl.

In some embodiments, R² is fluoromethyl.

In some embodiments, R² is isobutyl.

In some embodiments, R² is isopentyl.

In some embodiments, R² is isopropyl.

In some embodiments, R² is methoxymethyl.

In some embodiments, R² is methyl.

In some embodiments, R² is oxetan-3-yl.

In some embodiments, R² is propan-1-yl.

In some embodiments, R² is sec-butyl.

In some embodiments, R² is vinyl.

The R^(3a), R^(3b), R^(3c), and R^(3d) Groups

In some embodiments, R^(3a), R^(3b), R^(3c), and R^(3d) are eachindependently H or halogen.

In some embodiments, R^(3a) is H or halogen; R^(3b) is H; R^(3c) is H orhalogen; and R^(3d) is H.

In some embodiments, R^(3a) is halogen; R^(3b) is H; R^(3c) is H orhalogen; and R^(3d) is H.

In some embodiments, R^(3a) is H; R^(3b) is H; R^(3c) is halogen; andR^(3d) is H.

In some embodiments, R^(3a), R^(3b), R^(3c), and R^(3d) are eachindependently H or F.

In some embodiments, R^(3a) is H or F; R^(3b) is H; R^(3c) is H or F;and R^(3d) is H.

In some embodiments, R^(3a) is F; R^(3b) is H; R^(3c) is H; and R^(3d)is H.

In some embodiments, R^(3a) is H; R^(3b) is H; R^(3c) is F; and R^(3d)is H.

In some embodiments, R^(3a), R^(3b), R^(3c), and R^(3d) are each H.

In some embodiments, R^(3a) is halogen.

In some embodiments, R^(3b) is halogen.

In some embodiments, R^(3c) is halogen.

In some embodiments, R^(3d) is halogen.

In some embodiments, R^(3a) is F.

In some embodiments, R^(3b) is F.

In some embodiments, R^(3c) is F.

In some embodiments, R^(3d) is F.

In some embodiments, R^(3a) is H.

In some embodiments, R^(3b) is H.

In some embodiments, R^(3c) is H.

In some embodiments, R^(3d) is H.

Certain Combinations

One aspect of the present invention pertains to compounds of Formula(Ib) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein: R¹ (as well as Y and Z that are both related to R¹), X, W, R²,R^(3a), R^(3b), R^(3c), and R^(3d) all have the same definitions asdescribed herein, supra and infra.

One aspect of the present invention pertains to compounds of Formula(Ic) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

W is absent or —CH₂—;

R¹ is aryl or heteroaryl, wherein each is optionally substituted withone or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,amino, cyano, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen, hydroxyl, oxo,and sulfamoyl; and wherein said C₁-C₆ alkyl and C₃-C₇ cycloalkyl areeach optionally substituted with one or more substituents selected from:amino, C₁-C₆ alkoxy, C₁-C₆ alkylcarboxamide, —NH—C₃-C₇-cycloalkyl,—NH—C₁-C₆-alkylene-NH₂, —NH—C₁-C₆-alkylene-O—C₁-C₆-alkyl,—NH—C₁-C₆-alkylene-NH—C₁-C₆-alkyl, C₁-C₆ alkylamino, C₁-C₆haloalkylamino, and heterocyclyl;

R² is selected from: C₂-C₆ alkenyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,heterocyclyl, and C₁-C₆ haloalkyl; each optionally substituted with oneor more substituents selected from: C₁-C₆ alkoxy, C₁-C₆alkylenehydroxyl, amino, aryl, C₃-C₇ cycloalkyl, cyano, C₃-C₇halocycloalkyl, hydroxyl, and oxo; and

R^(3a), R^(3b), R^(3c), and R^(3d) are each independently H or halogen.

One aspect of the present invention pertains to compounds of Formula(Ic) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

W is absent or —CH₂—;

R¹ is selected from: (1H-pyrazolyl)phenyl, (1H-pyrazolyl)pyridinyl,(pyridinyl)phenyl, (pyrimidinyl)phenyl,1,2,3,4-tetrahydropyrido[3,2-b]pyrazinyl, 1,2-dihydroquinolinyl,1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl,1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl,2,3-dihydro-1H-imidazo[4,5-b]pyridinyl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,3,4-dihydro-2H-pyrano[2,3-b]pyridinyl,3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl,(phenyl)pyridinyl, 5,6,7,8-tetrahydronaphthalenyl,5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl,benzo[c][1,2,5]oxadiazolyl, benzofuranyl, biphenyl, chromanyl,isoquinolinyl, isoxazolyl, naphthalenyl, phenyl, phenylthiophenyl,pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl, and thiazolyl; whereineach is optionally substituted with one or more substituents selectedfrom: 2-methylpropan-2-yl, amino, bromo, chloro, cyclopropyl, ethoxy,ethyl, fluoro, hydroxy, isopropoxy, methoxy, methyl, oxo, propan-2-yl,propan-1-yl, sulfamoyl, and trifluoromethyl; and wherein said2-methylpropan-2-yl, cyclopropyl, ethyl, methyl, and propan-2-yl areeach optionally substituted with one or more substituents selected from:2,2,2-trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino,3-aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino,cyclobutylamino, ethylamino, isobutylamino, isopropylamino, methoxy,methylamino, morpholino, propylamino, tert-butylamino, andtert-pentylamino;

R² is selected from: 1,1-difluoroethyl, 1-fluoroethyl,2-methylpropan-2-yl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl,azetidin-3-yl, cyclobutyl, cyclopentyl, cyclopropyl, ethyl,fluoromethyl, isobutyl, isopentyl, isopropyl, methyl, oxetan-3-yl,propan-1-yl, sec-butyl, and vinyl; each optionally substituted with oneor more substituents selected from: 2,2-difluorocyclopropyl, amino,cyano, cyclobutyl, cyclohexyl, cyclopropyl, ethoxy, hydroxy,hydroxymethyl, methoxy, oxo, and phenyl; and

R^(3a), R^(3b), R^(3c), and R^(3d) are each independently H or F.

One aspect of the present invention pertains to compounds of Formula(Ic) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

W is absent or —CH₂—;

R¹ is selected from:(R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,(5)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl,1,4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl,1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-5-methyl-1H-pyrazol-4-yl,1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-6-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-8-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl, 1H-indol-2-yl, 1H-indol-3-yl,1H-indol-5-yl, 1H-indol-6-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl,1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl,1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-methyl-4-oxo-1,4-dihydroquinolin-3-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,2,3-dihydrobenzofuran-5-yl, 2-aminothiazol-4-yl,2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl,3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl,3-(1-ethyl-1H-pyrazol-4-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl,3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1H-pyrazol-4-yl)phenyl,3-(2-methylpyridin-4-yl)phenyl, 3-(3-fluoropyridin-2-yl)phenyl,3-(4-methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2-yl)phenyl,3-(6-(trifluoromethyl)pyridin-2-yl)phenyl,3-(6-aminopyridin-3-yl)phenyl, 3-(6-fluoropyridin-2-yl)phenyl,3-(6-methylpyridin-2-yl)phenyl, 3-(pyridin-2-yl)phenyl,3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl,3-(pyrimidin-5-yl)phenyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl,3,5-dimethylisoxazol-4-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl,3-methyl-3H-imidazo[4,5-b]pyridin-6-yl,3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-(pyridin-2-yl)phenyl,4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl,4-hydroxy-6-methylquinolin-3-yl, 4-hydroxy-7-methylquinolin-3-yl,4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl,4-methoxyquinolin-3-yl, 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl,4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl,4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl,4-oxo-1,4-dihydroquinolin-3-yl,5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl,5-(4-(aminomethyl)phenyl)pyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl,5-bromo-6-chloropyridin-3-yl, 5-bromopyridin-3-yl,5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 5-phenylthiophen-2-yl,6-fluoro-4-hydroxyquinolin-3-yl, 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl,7-fluoro-4-hydroxyquinolin-3-yl, 8-fluoro-4-hydroxyquinolin-3-yl,benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, chroman-7-yl,isoquinolin-5-yl, pyridin-2-yl, pyridin-3-yl,pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinolin-6-yl, andquinolin-7-yl;

R² is selected from: (2,2-difluorocyclopropyl)methyl,1-(hydroxymethyl)cyclobutyl, 1-(hydroxymethyl)cyclopropyl,1,1-difluoro-2-hydroxyethyl, 1-amino-2-methyl-1-oxopropan-2-yl,1-ethoxy-2-methyl-1-oxopropan-2-yl, 1-fluoroethyl,1-hydroxy-2-methylpropan-2-yl, 2-amino-2-oxoethyl, 2-aminoethyl,2-hydroxyethyl, 3,3,3-trifluoropropyl, 3-amino-3-oxopropyl,3-hydroxycyclobutyl, 3-hydroxypropyl, 3-methoxypropyl,4,4,4-trifluorobutyl, azetidin-3-yl, benzyl, carboxymethyl, cyanomethyl,cyclobutyl, cyclobutylmethyl, cyclohexylmethyl, cyclopentyl,cyclopropyl, cyclopropylmethyl, ethyl, fluoromethyl, isobutyl,isopentyl, isopropyl, methoxymethyl, methyl, oxetan-3-yl, propan-1-yl,sec-butyl, and vinyl; and

R^(3a), R^(3b), R^(3c), and R^(3d) are each independently H or F.

One aspect of the present invention pertains to compounds of Formula(Ie) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

R¹ is aryl or heteroaryl, wherein each is optionally substituted withone or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,amino, cyano, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen, hydroxyl, oxo,and sulfamoyl; and wherein said C₁-C₆ alkyl and C₃-C₇ cycloalkyl areeach optionally substituted with one or more substituents selected from:amino, C₁-C₆ alkoxy, C₁-C₆ alkylcarboxamide, —NH—C₃-C₇-cycloalkyl,—NH—C₁-C₆-alkylene-NH₂, —NH—C₁-C₆-alkylene-O—C₁-C₆-alkyl,—NH—C₁-C₆-alkylene-NH—C₁-C₆-alkyl, C₁-C₆ alkylamino, C₁-C₆haloalkylamino, and heterocyclyl;

R² is selected from: C₂-C₆ alkenyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,heterocyclyl, and C₁-C₆ haloalkyl; each optionally substituted with oneor more substituents selected from: C₁-C₆ alkoxy, C₁-C₆alkylenehydroxyl, amino, aryl, C₃-C₇ cycloalkyl, cyano, C₃-C₇halocycloalkyl, hydroxyl, and oxo; and

R^(3a) and R^(3c) are each independently H or halogen.

One aspect of the present invention pertains to compounds of Formula(Ie) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

R¹ is selected from: (1H-pyrazolyl)phenyl, (1H-pyrazolyl)pyridinyl,(pyridinyl)phenyl, (pyrimidinyl)phenyl,1,2,3,4-tetrahydropyrido[3,2-b]pyrazinyl, 1,2-dihydroquinolinyl,1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl,1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl,2,3-dihydro-1H-imidazo[4,5-b]pyridinyl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,3,4-dihydro-2H-pyrano[2,3-b]pyridinyl,3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl,(phenyl)pyridinyl, 5,6,7,8-tetrahydronaphthalenyl,5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl,benzo[c][1,2,5]oxadiazolyl, benzofuranyl, biphenyl, chromanyl,isoquinolinyl, isoxazolyl, naphthalenyl, phenyl, phenylthiophenyl,pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl, and thiazolyl; whereineach is optionally substituted with one or more substituents selectedfrom: 2-methylpropan-2-yl, amino, bromo, chloro, cyclopropyl, ethoxy,ethyl, fluoro, hydroxy, isopropoxy, methoxy, methyl, oxo, propan-2-yl,propan-1-yl, sulfamoyl, and trifluoromethyl; and wherein said2-methylpropan-2-yl, cyclopropyl, ethyl, methyl, and propan-2-yl areeach optionally substituted with one or more substituents selected from:2,2,2-trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino,3-aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino,cyclobutylamino, ethylamino, isobutylamino, isopropylamino, methoxy,methylamino, morpholino, propylamino, tert-butylamino, andtert-pentylamino;

R² is selected from: 1,1-difluoroethyl, 1-fluoroethyl,2-methylpropan-2-yl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl,azetidin-3-yl, cyclobutyl, cyclopentyl, cyclopropyl, ethyl,fluoromethyl, isobutyl, isopentyl, isopropyl, methyl, oxetan-3-yl,propan-1-yl, sec-butyl, and vinyl; each optionally substituted with oneor more substituents selected from: 2,2-difluorocyclopropyl, amino,cyano, cyclobutyl, cyclohexyl, cyclopropyl, ethoxy, hydroxy,hydroxymethyl, methoxy, oxo, and phenyl; and

R^(3a) and R^(3c) are each independently H or F.

One aspect of the present invention pertains to compounds of Formula(Ie) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

R¹ is selected from:(R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,(S)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl,1,4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl,1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-5-methyl-1H-pyrazol-4-yl,1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-6-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl,1-ethyl-8-methyl-4-oxo-1,4-dihydroquinolin-3-yl,1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl, 1H-indol-2-yl, 1H-indol-3-yl,1H-indol-5-yl, 1H-indol-6-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl,1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl,1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,1-methyl-4-oxo-1,4-dihydroquinolin-3-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,2,3-dihydrobenzofuran-5-yl, 2-aminothiazol-4-yl,2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl,3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl,3-(1-ethyl-1H-pyrazol-4-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl,3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1H-pyrazol-4-yl)phenyl,3-(2-methylpyridin-4-yl)phenyl, 3-(3-fluoropyridin-2-yl)phenyl,3-(4-methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2-yl)phenyl,3-(6-(trifluoromethyl)pyridin-2-yl)phenyl,3-(6-aminopyridin-3-yl)phenyl, 3-(6-fluoropyridin-2-yl)phenyl,3-(6-methylpyridin-2-yl)phenyl, 3-(pyridin-2-yl)phenyl,3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl,3-(pyrimidin-5-yl)phenyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl,3,5-dimethylisoxazol-4-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl,3-methyl-3H-imidazo[4,5-b]pyridin-6-yl,3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-(pyridin-2-yl)phenyl,4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl,4-hydroxy-6-methylquinolin-3-yl, 4-hydroxy-7-methylquinolin-3-yl,4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl,4-methoxyquinolin-3-yl, 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl,4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl,4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl,4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl,4-oxo-1,4-dihydroquinolin-3-yl,5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl,5-(4-(aminomethyl)phenyl)pyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl,5-bromo-6-chloropyridin-3-yl, 5-bromopyridin-3-yl,5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 5-phenylthiophen-2-yl,6-fluoro-4-hydroxyquinolin-3-yl, 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl,7-fluoro-4-hydroxyquinolin-3-yl, 8-fluoro-4-hydroxyquinolin-3-yl,benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, chroman-7-yl,isoquinolin-5-yl, pyridin-2-yl, pyridin-3-yl,pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinolin-6-yl, andquinolin-7-yl;

R² is selected from: (2,2-difluorocyclopropyl)methyl,1-(hydroxymethyl)cyclobutyl, 1-(hydroxymethyl)cyclopropyl,1,1-difluoro-2-hydroxyethyl, 1-amino-2-methyl-1-oxopropan-2-yl,1-ethoxy-2-methyl-1-oxopropan-2-yl, 1-fluoroethyl,1-hydroxy-2-methylpropan-2-yl, 2-amino-2-oxoethyl, 2-aminoethyl,2-hydroxyethyl, 3,3,3-trifluoropropyl, 3-amino-3-oxopropyl,3-hydroxycyclobutyl, 3-hydroxypropyl, 3-methoxypropyl,4,4,4-trifluorobutyl, azetidin-3-yl, benzyl, carboxymethyl, cyanomethyl,cyclobutyl, cyclobutylmethyl, cyclohexylmethyl, cyclopentyl,cyclopropyl, cyclopropylmethyl, ethyl, fluoromethyl, isobutyl,isopentyl, isopropyl, methoxymethyl, methyl, oxetan-3-yl, propan-1-yl,sec-butyl, and vinyl; and

R^(3a) and R^(3c) are each independently H or F.

One aspect of the present invention pertains to compounds of Formula(Ig) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

Ar¹ and Ar² are independently 1H-pyrazolyl, phenyl, pyridinyl,pyrimidinyl, and thiophenyl, wherein each is optionally substituted withone or more substituents selected from: C₁-C₆ alkoxy, C₁-C₆ alkyl,amino, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, halogen, and sulfamoyl; andwherein said C₁-C₆ alkyl and C₃-C₇ cycloalkyl are each optionallysubstituted with one or more substituents selected from: amino, C₁-C₆alkylcarboxamide, —NH—C₃-C₇-cycloalkyl, —NH—C₁-C₆-alkylene-NH₂,—NH—C₁-C₆-alkylene-O—C₁-C₆-alkyl, C₁-C₆ alkylamino, C₁-C₆haloalkylamino, and heterocyclyl;

R² is selected from: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and C₁-C₆ haloalkyl;each optionally substituted with one or more substituents selected from:C₁-C₆ alkoxy, C₁-C₆ alkylenehydroxyl, amino, hydroxyl, and oxo; and

R^(3a), R^(3b), R^(3c), and R^(3d) are each independently H or halogen.

One aspect of the present invention pertains to compounds of Formula(Ig) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

Ar¹ and Ar² together form a group selected from: (1H-pyrazolyl)phenyl,(1H-pyrazolyl)pyridinyl, (phenyl)pyridinyl, (pyridinyl)phenyl,(pyrimidinyl)phenyl, biphenyl, and phenylthiophenyl, wherein each isoptionally substituted with one or more substituents selected from:2-methylpropan-2-yl, amino, cyclopropyl, ethoxy, ethyl, fluoro,isopropoxy, methoxy, methyl, n-propyl, propan-2-yl, sulfamoyl, andtrifluoromethyl; and wherein said 2-methylpropan-2-yl, cyclopropyl,ethyl, methyl, and propan-2-yl are each optionally substituted with2,2,2-trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino,3-aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino,cyclobutylamino, ethylamino, isobutylamino, isopropylamino,isopropylamino, methylamino, morpholino, propylamino, tert-butylamino,and tert-pentylamino;

R² is selected from: 1,1-difluoroethyl, 2-methylpropan-2-yl,cyclopropyl, ethyl, isopropyl, and methyl; each optionally substitutedwith one or more substituents selected from: amino, hydroxy,hydroxymethyl, methoxy, and oxo; and

R^(3a), R^(3b), R^(3c), and R^(3d) are each H.

One aspect of the present invention pertains to compounds of Formula(Ig) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

Ar¹ and Ar² together form a group selected from:3-(1H-pyrazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl,3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl,3-(pyrimidin-5-yl)phenyl, 4-(pyridin-2-yl)phenyl,4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl,5-(1H-pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl,5-phenylthiophen-2-yl, biphenyl-3-yl, and biphenyl-4-yl, wherein each isoptionally substituted with one or more substituents selected from:(2,2,2-trifluoroethylamino)methyl, (2-aminoethylamino)methyl,(2-methoxyethylamino)methyl, (3-aminopropylamino)methyl,(butylamino)methyl, (cyclobutylamino)methyl, (ethylamino)methyl,(isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl,(propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl,1-amino-2-methylpropan-2-yl, 1-aminocyclopropyl, 2-acetamidoethyl,2-aminoethyl, 2-aminopropan-2-yl, amino, aminomethyl,azetidin-1-ylmethyl, cyclopropyl, ethoxy, ethyl, fluoro, isopropoxy,methoxy, methyl, morpholinomethyl, propyl, sulfamoyl, andtrifluoromethyl;

R² is selected from: 1-(hydroxymethyl)cyclopropyl,1,1-difluoro-2-hydroxyethyl, 1-hydroxy-2-methylpropan-2-yl,2-amino-2-oxoethyl, 2-hydroxyethyl, cyclopropyl, ethyl, isopropyl,methoxymethyl, and methyl; and

R^(3a), R^(3b), R^(3c), and R^(3d) are each H.

One aspect of the present invention pertains to compounds of Formula(Ig) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

Ar¹ and Ar² together form a group selected from:3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl,3-(1-ethyl-1H-pyrazol-4-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl,3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1H-pyrazol-4-yl)phenyl,3-(2-methylpyridin-4-yl)phenyl, 3-(3-fluoropyridin-2-yl)phenyl,3-(4-methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2-yl)phenyl,3-(6-(trifluoromethyl)pyridin-2-yl)phenyl,3-(6-aminopyridin-3-yl)phenyl, 3-(6-fluoropyridin-2-yl)phenyl,3-(6-methylpyridin-2-yl)phenyl, 3-(pyridin-2-yl)phenyl,3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl,3-(pyrimidin-5-yl)phenyl,4′-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl,4′-((2-aminoethylamino)methyl)biphenyl-3-yl,4′-((2-methoxyethylamino)methyl)biphenyl-3-yl,4′-((3-aminopropylamino)methyl)biphenyl-3-yl,4′-((butylamino)methyl)biphenyl-3-yl,4′-((cyclobutylamino)methyl)biphenyl-3-yl,4′-((ethylamino)methyl)biphenyl-3-yl,4′-((isobutylamino)methyl)biphenyl-3-yl,4′-((isopropylamino)methyl)biphenyl-3-yl,4′-((methylamino)methyl)biphenyl-3-yl,4′-((propylamino)methyl)biphenyl-3-yl,4′-((tert-butylamino)methyl)biphenyl-3-yl,4′-((tert-pentylamino)methyl)biphenyl-3-yl,4′-(1-amino-2-methylpropan-2-yl)-4-ethoxybiphenyl-3-yl,4′-(1-amino-2-methylpropan-2-yl)biphenyl-3-yl,4′-(1-aminocyclopropyl)-2-methylbiphenyl-3-yl,4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-yl,4′-(1-aminocyclopropyl)-6-fluorobiphenyl-3-yl,4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl,4′-(1-aminocyclopropyl)biphenyl-3-yl,4′-(2-acetamidoethyl)-4-ethoxy-biphenyl-3-yl,4′-(2-acetamidoethyl)-biphenyl-3-yl,4′-(2-aminoethyl)-4-ethoxybiphenyl-3-yl,4′-(2-aminoethyl)-6-methoxybiphenyl-3-yl,4′-(2-aminoethyl)biphenyl-3-yl,4′-(2-aminopropan-2-yl)-4-ethoxybiphenyl-3-yl,4′-(aminomethyl)-2-methoxybiphenyl-3-yl,4′-(aminomethyl)-2-methylbiphenyl-3-yl,4′-(aminomethyl)-3′-fluorobiphenyl-3-yl,4′-(aminomethyl)-4-ethoxy-3′-fluorobiphenyl-3-yl,4′-(aminomethyl)-4-ethoxybiphenyl-3-yl,4′-(aminomethyl)-4-fluorobiphenyl-3-yl,4′-(aminomethyl)-4-isopropoxybiphenyl-3-yl,4′-(aminomethyl)-5-methoxybiphenyl-3-yl,4′-(aminomethyl)-6-ethoxybiphenyl-3-yl,4′-(aminomethyl)-6-fluorobiphenyl-3-yl,4′-(aminomethyl)-6-methoxybiphenyl-3-yl, 4′-(aminomethyl)biphenyl-3-yl,4′-(aminomethyl)biphenyl-4-yl, 4′-(azetidin-1-ylmethyl)biphenyl-3-yl,4′-(morpholinomethyl)biphenyl-3-yl, 4-(pyridin-2-yl)phenyl,4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl,4′-(sulfamoyl)biphenyl-3-yl,4-ethoxy-4′-((isopropylamino)methyl)biphenyl-3-yl,4′-methylbiphenyl-3-yl, 5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl,5-(4-(aminomethyl)phenyl)pyridin-3-yl, and 5-phenylthiophen-2-yl;

R² is selected from: 1-(hydroxymethyl)cyclopropyl,1,1-difluoro-2-hydroxyethyl, 1-hydroxy-2-methylpropan-2-yl,2-amino-2-oxoethyl, 2-hydroxyethyl, cyclopropyl, ethyl, isopropyl,methoxymethyl, and methyl; and

R^(3a), R^(3b), R^(3c), and R^(3d) are each H.

One aspect of the present invention pertains to compounds of Formula(Ii) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

R² is selected from: C₁-C₆ alkyl, C₃-C₇ cycloalkyl, and C₁-C₆ haloalkyl;each optionally substituted with one or more substituents selected from:C₁-C₆ alkoxy, C₁-C₆ alkylenehydroxyl, and hydroxyl;

R^(3a), R^(3b), R^(3c), and R^(3d) are each independently H or halogen;

R⁴ is H or C₁-C₆ alkyl; and

R^(5a), R^(5b), R^(5c), and R^(5d) are independently H, C₁-C₆ alkyl, andhalogen.

One aspect of the present invention pertains to compounds of Formula(Ii) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

R² is selected from: 1,1-difluoroethyl, 2-methylpropan-2-yl,cyclopropyl, ethyl, 1-fluoroethyl, isopropyl, and methyl; eachoptionally substituted with one or more substituents selected from:hydroxy, hydroxymethyl, and methoxy;

R^(3a), R^(3b), R^(3c), and R^(3d) are each H;

R⁴ is selected from: H, methyl, and ethyl; and

R^(5a), R^(5b), R^(5c), and R^(5d) are independently H, methyl, andfluoro.

One aspect of the present invention pertains to compounds of Formula(Ii) and pharmaceutically acceptable salts, solvates, and hydratesthereof:

wherein:

R² is selected from: 1-(hydroxymethyl)cyclopropyl,1,1-difluoro-2-hydroxyethyl, 1-fluoroethyl,1-hydroxy-2-methylpropan-2-yl, cyclopropyl, isopropyl, methoxymethyl,and methyl;

R^(3a), R^(3b), R^(3c), and R^(3d) are each H;

R⁴ is selected from: H, methyl, and ethyl;

R^(5a), R^(5b), and R^(5c) are independently H, methyl, and fluoro; and

R^(5d) is H.

Some embodiments of the present invention include every combination ofone or more compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof selected from the following group shown in Table A.

TABLE A Cmpd No. Chemical Structure Chemical Name 5

(2S)-1-(3-(2- hydroxyethylsulfonyl) phenoxy)-3-(8- (naphthalen-2-ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3- ylamino)propan-2-ol 88

(S)-1-(3-(2- hydroxyethylsulfonyl) phenoxy)-3-(R)-8-(quinolin-3-ylsulfonyl)- 1-oxa-8- azaspiro[4.5]decan-3-ylamino)propan-2-ol 123

2-(3-((S)-2-hydroxy-3- ((R)-8-(quinolin-3- ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3- ylamino)propoxy)phenyl sulfonl)acetamide 136

(S)-1-(3-(1- (hydroxymethyl) cyclopropylsulfonyl) phenoxy)-3-((R)-8-(quinolin-3- ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3-ylamino)propan-2-ol 154

(S)-1-(3-(cyclopropyl- sulfonyl)phenoxy)- 3-((R)-8-(l-methyl-2,3-dihydro-1H-pyrido [2,3-b][1,4]oxazin-7- ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3- ylamino)propan-2-ol 161

(S)-1-((R)-8-(4′- (aminomethyl)-4- ethoxybiphenyl-3-ylsulfonyl)-l-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(1,1-difluoro-2- hydroxyethylsulfonyl) phenoxy)propan-2-ol 163

(S)-1-((S)-8-(4′- (aminomethyl)-4- ethoxybiphenyl-3-ylsulfonyl)-l-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(1-(hydroxymethyl) cyclopropylsulfonyl) phenoxy)propan-2-ol 169

(S)-1-((R)-8-(4′- (aminomethyl)-4- fluorobiphenyl-3-ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(1-(hydroxymethyl) cyclopropylsulfonyl) phenoxy)propan-2-ol 199

(S)-1-((R)-8-(4′-(1- aminocyclopropyl)-6- methoxybiphenyl-3-ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(1-(hydroxymethyl) cyclopropylsulfonyl (phenoxy)propan-2-ol 210

(S)-1-((S)-8-(4′-(2- aminoethyl)biphenyl-3- ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3- ylamino)-3-(3-(1,1- difluoro-2-hydroxyethylsulfonyl) phenoxy)propan-2-ol 211

(S)-1-((S)-8-(4′-(2- aminoethyl)biphenyl-3- ylsulfonyl)-l-oxa-8-azaspiro[4.5]decan-3- ylamino)-3-(3-(1- (hydroxymelhyl)cyclopropylsulfonyl) phenoxy)propan-2-ol 217

(S)-1-((R)-8-(4′-(1- aminocyclopropyl)-6- fluorobiphenyl-3-ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(1-(hydroxymethyl) cyclopropylsulfonyl) phenoxy)propan-2-ol 220

(S)-1-((S)-8-(4′- (aminomethyl)-4- ethoxy-3′- fluorobiphenyl-3-ylsulfonyl)-l-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(1-(hydroxymethyl) cyclopropylsulfonyl) phenoxy)propan-2-ol 225

(S)-1-((S)-8-(4′-(1- aminocyclopropyl)-6- methoxybiphenyl-3-ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(1-(hydroxymethyl) cyclopropylsulfonyl) phenoxy)propan-2-ol 227

(S)-1-((S)-8-(4′- (aminomethyl)-6- methoxybiphenyl-3-ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(cyclopropylsulfonyl) phenoxy)propan-2-ol 229

(S)-1-((S)-8-(4′- (aminomethyl)-5- methoxybiphenyl-3-ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(cyclopropylsulfonyl) phenoxy)propan-2-ol 230

(S)-1-((S)-8-(4′- (aminomethyl)-4- ethoxybiphenyl-3-ylsulfonyl)-l-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(methoxymethylsulfonyl) phenoxy)propan-2-ol 232

(S)-1-((S)-8-(4′- (aminomethyl)-4- ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(isopropylsulfonyl) phenoxy)propan-2-ol 234

(2S)-1-(3-(1- fluoroethylsulfonyl) phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)- 1-oxa-8- azaspiro[4.5]decan-3-ylamino)propan-2-ol 240

(S)-1-((S)-8-(4′-((tert- butylamino(methyl) biphenyl-3-ylsulfonyl)-l-oxa-8- azaspiro[4.5]decan-3- ylamino)-3-(3-(1- (hydroxymethyl)cyclopropylsulfonyl) phcnoxy)propan-2-ol 241

(S)-1-(3-(1- (hydroxymelhyl) cyclopropylsulfonyl) phenoxy)-3-((S)-8-(4′-((tertpentylamino) melhyl)biphenyl-3- ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3- ylamino)propan-2-ol 243

(S)-1-((S)-8-(4′- (azetidin-1- ylmethyl)biphenyl-3- ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3- ylamino)-3-(3-(1- (hydroxymethyl)cyclopropylsulfonyl) phenoxy)propan-2-ol 244

(S)-l-(3-(l- (hydroxymethyl) cyclopropylsulfonyl) phcnoxy)-3-((S)-8-(4′-((propylamino)methyl) biphenyl-3-ylsulfonyl)- 1-oxa-8-azaspiro[4.5]decan-3- ylamino)propan-2-ol 245

(S)-1-((S)-8-(4′- ((butylamino)methyl) biphenyl-3-ylsulfonyl)- 1-oxa-8-azaspiro[4.5]decan-3- ylamino)-3-(3-(1- (hydroxymethyl)cyclopropylsulfonyl) phenoxy)propan-2-ol 247

(S)-1-(3-(1- (hydroxymethyl) cyclopropylsulfonyl) phenoxy)-3-((S)-8-(4′-((2- melhoxyethylamino) methyl)biphenyl-3-ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3- ylamino)propan-2-ol 296

1-ethyl-3-((S)-3-((R)-2- hydroxy-3-(3- (methylsulfonyl)phenoxy)propylamino)-1-oxa- 8-azaspiro[4.5]decan-8- ylsulfonyl)quinolin-4(1H)-one 297

3-((R)-3-((S)-3-(3- (cyclopropylsulfonyl) phenoxy)-2-hydroxypropylamino)- 1-oxa-8- azaspiro[4.5]decan-8- ylsulfonyl)-1-ethylquinolin-4(1H)-one 300

(S)-1-(3-(1- (hydroxymethyl) cyclopropylsulfonyl) phenoxy)-3-((R)-8-(naphthalen-2- ylsulfonyl)-1-oxa-8- azaspiro[4.5]decan-3-ylamino)propan-2-ol 309

(S)-1-((R)-8-(1H- pyrrolo[3,2-b]pyridin-6- ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3- ylamino)-3-(3- (cyclopropylsulfonyl)phenoxy)propan-2-ol 310

1-ethyl-3-((R)-3-((S)-2- hydroxy-3-(3- (methylsulfonyl)phenoxy)propylamino)-1-oxa- 8-azaspiro[4.5]decan-8- ylsulfonyl)quinolin-4(1H)-one 320

(S)-1-((R)-8-(1H- pyrrolo[3,2-b]pyridin-6- ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3- ylamino)-3-(3- (mcthylsulfonyl)phenoxy)propan-2-ol 321

(S)-1-((R)-8-(1H- pyrrolo[3,2-b]pyridin-6- ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3- ylamino)-3-(3- (isopropylsulfonyl)phcnoxy)propan-2-ol 322

1-ethyl-8-fluoro-3-((R)- 3-((S)-2-hydroxy-3-(3- (methylsulfonyl)phenoxy)propylamino)-1-oxa- 8-azaspiro[4.5]decan-8- ylsulfonyl)quinolin-4(1H)-one 326

3-((R)-3-((S)-3-(3- (cyclopropylsulfonyl) phenoxy)-2-hydroxypropylamino)-1- oxa-8-azaspiro[4.5]decan- 8-ylsulfonyl)quinolin-4(1H)-one 327

3-((R)-3-((S)-3-(3- (cyclopropylsulfonyl) phenoxy)-2-hydroxypropylamino)-1- oxa-8-azaspiro[4.5]decan- 8-ylsulfonyl)-8-methylquinolin-4-ol 329

3-((R)-3-((S)-3-(3- (cyclopropylsulfonyl) phenoxy)-2-hydroxypropylamino)-1- oxa-8-azaspiro[4.5]decan- 8-ylsulfonyl)-7-fluoroquinolin-4-ol 331

1-ethyl-8-fluoro-3-((R)- 3-((S)-2-hydroxy-3-(3- (isopropylsulfonyl)phenoxy)propylamino)- 1-oxa-8- azaspiro[4.5]decan-8-ylsulfonyl)quinolin- 4(1H)-one

Some embodiments of the present invention include every combination ofone or more compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof selected from the following group, wherein theCompound Number in bold directly preceding the chemical name is usedelsewhere in this disclosure:

Compound 5:(2S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 88:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 123:2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)acetamide;Compound 136:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 154:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 161:(S)-1-((R)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 163:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 169:(S)-1-((R)-8-(4′-(aminomethyl)-4-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 199:(S)-1-((R)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 210:(S)-1-((S)-8-(4′-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 211:(S)-1-((S)-8-(4′-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 217:(S)-1-((R)-8-(4′-(1-aminocyclopropyl)-6-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 220:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxy-3′-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 225:(S)-1-((S)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 227:(S)-1-((S)-8-(4′-(aminomethyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 229:(S)-1-((S)-8-(4′-(aminomethyl)-5-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 230:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methoxymethylsulfonyl)phenoxy)propan-2-ol;Compound 232:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(isopropylsulfonyl)phenoxy)propan-2-ol;Compound 234:(2S)-1-(3-(1-fluoroethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 240:(S)-1-((S)-8-(4′-((tert-butylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 241:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4′-((tert-pentylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 243:(S)-1-((S)-8-(4′-(azetidin-1-ylmethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 244:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4′-((propylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 245:(S)-1-((S)-8-(4′-((butylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 247:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4′-((2-methoxyethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 296:1-ethyl-3-((S)-3-((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 297:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethylquinolin-4(1H)-one;Compound 300:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 309:(S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 310:1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 320:(S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 321:(S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(isopropylsulfonyl)phenoxy)propan-2-ol;Compound 322:1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 326:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 327:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-8-methylquinolin-4-ol;Compound 329:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-7-fluoroquinolin-4-ol;and Compound 331:1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one.

Some embodiments of the present invention include every combination ofone or more compounds and pharmaceutically acceptable salts, solvates,and hydrates thereof selected from the following group, wherein theCompound Number in bold directly preceding the chemical name is usedelsewhere in this disclosure:

Compound 1:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 2:(2R)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 3:(S)-1-(3-(methylsulfonyl)phenoxy)-3-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 4:(S)-1-(3-(methylsulfonyl)phenoxy)-3-((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 6:(2S)-1-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(propylsulfonyl)phenoxy)propan-2-ol;Compound 7:(2S)-1-(3-(cyclopropylmethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 8:(2S)-1-(3-(isopropylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 9:(2S)-1-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(3,3,3-trifluoropropylsulfonyl)phenoxy)propan-2-ol;Compound 10:(2S)-1-(3-(isobutylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 11:(2S)-1-(3-(isopentylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 12:2-(3-((2S)-2-hydroxy-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)acetonitrile;Compound 13:(2S)-1-(3-(cyclobutylmethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 14:(2S)-1-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(4,4,4-trifluorobutylsulfonyl)phenoxy)propan-2-ol;Compound 15:(2S)-1-(3-(ethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 16:(2S)-1-(3-(cyclohexylmethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 17:(2S)-1-(3-((2,2-difluorocyclopropyl)methylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 18:(2S)-1-(3-(cyclobutylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 19:(2S)-1-(3-(cyclopentylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 20:(2S)-1-(3-(benzylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 21:(2S)-1-(3-(azetidin-3-ylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 22:(2S)-1-(3-(2-aminoethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 23:(R)-1-(3-(methylsulfonyl)phenoxy)-3-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 24:(2S)-1-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(oxetan-3-ylsulfonyl)phenoxy)propan-2-ol;Compound 25:(2S)-1-(3-(sec-butylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 26:(S)-1-(3-(ethylsulfonyl)phenoxy)-3-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 27:(S)-1-(3-(ethylsulfonyl)phenoxy)-3-((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 28:(2S)-1-(8-(chroman-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 29:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(5,6,7,8-tetrahydronaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 30:(2S)-1-(8-(7-chlorobenzo[c][1,2,5]oxadiazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 31:(2S)-1-(8-(3-chlorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 32:(2S)-1-(8-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 33:(R)-1-(3-(methylsulfonyl)phenoxy)-3-((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 34:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 35:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 36:(2S)-1-(8-(3-(1-ethyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 37:(2S)-1-(8-(3-(1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 38:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(3-(1-propyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 39:(2S)-1-(8-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 40:(2S)-1-(8-(3-(1-methyl-1H-pyrazol-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 41:(2S)-1-(8-(4′-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 42:3′-(3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)biphenyl-4-sulfonamide;Compound 43:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(3-(pyridin-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 44:(2S)-1-(8-(3-(2-methylpyridin-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 45:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(3-(pyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 46:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 47:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 48:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(m-tolylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 49:(2S)-1-(8-(3-methoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 50:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(3-(trifluoromethyl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 51:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(5-phenylthiophen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 52:(2S)-1-(8-(3,5-dimethylisoxazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 53:6-(3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-2H-benzo[b][1,4]oxazin-3(4H)-one;Compound 54:(2S)-1-(8-(3-fluorophenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 55:3-(3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)benzonitrile;Compound 56:2-(2-aminothiazol-4-yl)-1-(3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-yl)ethanone;Compound 57:(3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-yl)(naphthalen-2-yl)methanone;Compound 58:(2S)-1-(8-(1-ethyl-5-methyl-1H-pyrazol-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 59:(2S)-1-(8-(5-chloronaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 60:(2S)-1-(8-(benzofuran-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 61:(2S)-1-(8-(benzofuran-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 62:(2S)-1-(8-(1H-indol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 63:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(3-(pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 64:(3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-yl)(4-methyl-3,4-dihydro-2H-benzo[6][1,4]oxazin-7-yl)methanone;Compound 65:(3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-yl)(1H-indol-2-yl)methanone;Compound 66:(3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-yl)(1H-indol-3-yl)methanone;Compound 67:(3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-yl)(1H-indol-5-yl)methanone;Compound 68:(3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-yl)(1H-indol-6-yl)methanone;Compound 69:(2S)-1-(8-(3-bromophenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 70:(2S)-1-(8-(3-(6-aminopyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 71:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(3-(pyrimidin-5-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 72:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(pyridin-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 73:(2S)-1-(8-(6-chloronaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 74:(2S)-1-(8-(2,3-dihydrobenzofuran-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 75:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 76:(2S)-1-(8-(1H-benzo[d]imidazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 77:(2,5)-1-(8-(1H-indazol-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 78:(2S)-1-(8-(4′-((methylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 79:(2S)-1-(8-(4′-((ethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 80:(2S)-1-(8-(4′-((isopropylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 81:(2S)-1-(8-(4′-((isobutylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 82:(2S)-1-(3-(methylsulfonyl)phenoxy)-3-(8-(4′-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 83:(S)-1-((R)-8-(chroman-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 84:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(4-methyl-3,4-dihydro-2H-benzo[6][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 85:(S)-1-(3-(methylsulfonyl)phenoxy)-3-((S)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 86:(2S)-1-(3-(fluoromethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 87:(S)-1-((R)-8-(chroman-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 88:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 89:(S)-1-((R)-8-(5-(4-(aminomethyl)phenyl)pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 90:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 91:(S)-1-((R)-8-(4′-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 92:(S)-1-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(vinylsulfonyl)phenoxy)propan-2-ol;Compound 93:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 94:(2R)-1-(3-(methylsulfonylmethyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 95:(S)-1-(3-(methylsulfonylmethyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 96:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(3-(pyridin-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 97:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(3-(pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 98:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 99:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(4-(pyridin-3-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 100:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(3-(pyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 101:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(4-(pyridin-4-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 102:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(4-(pyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 103:(S)-1-((R)-8-(4′-(aminomethyl)biphenyl-4-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 104:(S)-1-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonylmethyl)phenoxy)propan-2-ol;Compound 105:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(isoquinolin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 106:2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)-2-methylpropan-1-ol;Compound 107:(S)-1-(3-(1-(hydroxymethyl)cyclobutylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 108:2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)-2-methylpropanamide;Compound 109:2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)-2-methylpropan-1-ol;Compound 110:(S)-1-(3-(1-(hydroxymethyl)cyclobutylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 111:(S)-1-(3-(methylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 112:(S)-1-(3-(ethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 113:(S)-1-(3-(isopropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 114:(S)-1-(3-(cyclobutylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 115:(S)-1-(3-(propylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 116:(S)-1-(3-(isobutylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 117:(S)-1-(3-(cyclopropylmethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 118:(S)-1-(3-(methylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 119:(S)-1-(3-(isopropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 120:(5)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((S)-8-(3-(6-methylpyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 121:3-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)propan-1-ol;Compound 122:(S)-1-(3-(ethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 123:2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)acetamide;Compound 124:(S)-1-(3-(isobutylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 125:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(3-(6-(trifluoromethyl)pyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 126:(S)-1-((R)-8-(3-(3-fluoropyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 127:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(3-(5-methylpyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 128:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(3-(6-methylpyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 129:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(3-(4-methylpyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 130:(S)-1-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 131:(S)-1-(3-(methoxymethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 132:(S)-1-(3-(3-methoxypropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 133:3-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)propanamide;Compound 134:(S)-1-((R)-8-(3-(6-fluoropyridin-2-yl)phenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 135:3-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)propan-1-ol;Compound 136:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 137:2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)acetamide;Compound 138:(S)-1-(3-(cyclobutylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 139:(S)-1-(3-(propylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 140:(S)-1-(3-(cyclopropylmethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 141:(S)-1-(3-(methoxymethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 142:3-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)propanamide;Compound 143:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 144:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 145: ethyl2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)-2-methylpropanoate;Compound 146:3-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)cyclobutanol;Compound 147:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 148:(S)-1-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 149:(S)-1-(3-(3-methoxypropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 150:3-(3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)propan-1-ol;Compound 151:(S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 152:(S)-1-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 153:(S)-1-(3-(isopropylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 154:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 155:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 156:(S)-1-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 157:(S)-1-((R)-8-(4′-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 158:(S)-1-((R)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 159:2-(3-((S)-2-hydroxy-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)acetamide;Compound 160:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 161:(S)-1-((R)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 162:(S)-1-((S)-8-(4′-(aminomethyl)-4-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 163:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 164:(S)-1-((S)-8-(4′-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 165:(S)-1-((R)-8-(4-ethoxy-4′-((isopropylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 166:(S)-1-((S)-8-(4′-(aminomethyl)-4-isopropoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 167:(S)-1-((R)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 168:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 169:(S)-1-((R)-8-(4′-(aminomethyl)-4-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 170:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(4′-methylbiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 171:(S)-1-((R)-8-(4′-(aminomethyl)-4-isopropoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 172:(S)-1-((R)-8-(4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 173:(S)-1-((R)-8-(4′-(1-aminocyclopropyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 174:(S)-1-((R)-8-(4′-(1-amino-2-methylpropan-2-yl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 175:N-(2-(4′-ethoxy-3′-((R)-3-((S)-2-hydroxy-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)biphenyl-4-yl)ethyl)acetamide;Compound 176:(S)-1-((S)-8-(4′-(1-amino-2-methylpropan-2-yl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 177:N-(2-(4′-ethoxy-3′-((S)-3-((S)-2-hydroxy-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)biphenyl-4-yl)ethyl)acetamide;Compound 178:2-(3-((S)-3-((R)-8-(4′-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-2-hydroxypropoxy)phenylsulfonyl)acetamide;Compound 179:2-(3-((S)-3-((R)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-2-hydroxypropoxy)phenylsulfonyl)acetamide;Compound 180:(S)-1-((S)-8-(4′-(1-amino-2-methylpropan-2-yl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 181:(S)-1-((R)-8-(4′-(1-amino-2-methylpropan-2-yl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 182:(S)-1-((S)-8-(4′-(aminomethyl)-3′-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 183:2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)aceticacid; Compound 184:(S)-1-((S)-8-(4′-(1-aminocyclopropyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 185:(S)-1-((R)-8-(5-bromopyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 186:(S)-1-((S)-8-(5-bromopyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 187:2-(3-((S)-3-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-2-hydroxypropoxy)phenylsulfonyl)-2-methylpropan-1-ol;Compound 188:(S)-1-((S)-8-(4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 189:(S)-1-((R)-8-(4′-(aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 190:N-(2-(3′-((S)-3-((S)-2-hydroxy-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)biphenyl-4-yl)ethyl)acetamide;Compound 191:N-(2-(3′-((R)-3-((S)-2-hydroxy-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)biphenyl-4-yl)ethyl)acetamide;Compound 192:(S)-1-((R)-8-(3-bromo-2-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 193:(S)-1-((R)-8-(3-bromo-4-methoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 194:(S)-1-((R)-8-(4-bromo-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 195:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 196:(S)-1-((S)-8-(4-bromo-3-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 197:(S)-1-((S)-8-(4′-(aminomethyl)-2-methylbiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 198:(S)-1-((S)-8-(4′-(1-aminocyclopropyl)-2-methylbiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 199:(S)-1-((R)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 200:(S)-1-((S)-8-(3-bromo-2-methylphenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 201:(S)-1-((S)-8-(3-bromo-4-methoxyphenylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 202:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 203:(S)-1-((R)-8-(4′-(aminomethyl)-2-methylbiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 204:(S)-1-((R)-8-(4′-(1-aminocyclopropyl)-2-methylbiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 205:2-(3-((S)-3-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-2-hydroxypropoxy)phenylsulfonyl)acetamide;Compound 206:2-(3-((S)-3-((S)-8-(4′-(aminomethyl)-2-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-2-hydroxypropoxy)phenylsulfonyl)acetamide;Compound 207:(S)-1-((S)-8-(4′-(aminomethyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 208:(S)-1-((R)-8-(4′-(aminomethyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 209:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 210:(S)-1-((S)-8-(4′-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 211:(S)-1-((S)-8-(4′-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 212:(S)-1-((R)-8-(4′-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 213:(S)-1-((R)-8-(4′-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 214:(S)-1-((S)-8-(4′-(2-aminoethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 215:(S)-1-((S)-8-(4′-(2-aminoethyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 216:(S)-1-((R)-8-(4′-(aminomethyl)-6-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 217:(S)-1-((R)-8-(4′-(1-aminocyclopropyl)-6-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 218:(S)-1-((S)-8-(4′-(aminomethyl)-6-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 219:(S)-1-((S)-8-(4′-(1-aminocyclopropyl)-6-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 220:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxy-3′-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 221:(S)-1-((R)-8-(5-bromo-6-chloropyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 222:(S)-1-((R)-8-(1,4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 223:2-(3-((S)-3-((S)-8-(4′-(aminomethyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-2-hydroxypropoxy)phenylsulfonyl)-2-methylpropan-1-ol;Compound 224:2-(3-((S)-3-((S)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-2-hydroxypropoxy)phenylsulfonyl)-2-methylpropan-1-ol;Compound 225:(S)-1-((S)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 226:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(ethylsulfonyl)phenoxy)propan-2-ol;Compound 227:(S)-1-((S)-8-(4′-(aminomethyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 228:(S)-1-((S)-8-(4′-(aminomethyl)-2-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 229:(S)-1-((S)-8-(4′-(aminomethyl)-5-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 230:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methoxymethylsulfonyl)phenoxy)propan-2-ol;Compound 231:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 232:(S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(isopropylsulfonyl)phenoxy)propan-2-ol;Compound 233:(2S)-1-(3-(1-fluoroethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 234:(2S)-1-(3-(1-fluoroethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 235:(2S)-1-(3-(1-fluoroethylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 236:6-((R)-3-((S)-2-hydroxy-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-4-methylquinolin-2(1H)-one;Compound 237:(S)-1-((S)-8-(4′-(aminomethyl)-6-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 238:(S)-1-((S)-8-(4′-(aminomethyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 239:(S)-1-((S)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol;Compound 240:(S)-1-((S)-8-(4′-((tert-butylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 241:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4′-((tert-pentylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 242:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4′-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 243:(S)-1-((S)-8-(4′-(azetidin-1-ylmethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 244:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4′-((propylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 245:(S)-1-((S)-8-(4′-((butylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 246:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4′-(morpholinomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 247:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4′-((2-methoxyethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 248:(S)-1-(3-fluoro-5-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 249:(S)-1-(3-fluoro-5-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 250:(S)-1-((S)-8-(1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 251:(S)-1-0.9)-8-(4′-(2-aminopropan-2-yl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 252:(S)-1-0.9)-8-(4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 253:(S)-1-((S)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 254:(S)-1-((R)-8-(4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 255:(S)-1-((R)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 256:(S)-1-((S)-8-(4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(ethylsulfonyl)phenoxy)propan-2-ol;Compound 257:(S)-1-((R)-8-(4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(ethylsulfonyl)phenoxy)propan-2-ol;Compound 258:(S)-1-((R)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(ethylsulfonyl)phenoxy)propan-2-ol;Compound 259:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 260:(S)-1-((R)-8-(1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 261:(S)-1-((S)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(ethylsulfonyl)phenoxy)propan-2-ol;Compound 262:(S)-1-((R)-8-(4′-((tert-butylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 263:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(4′-((tert-pentylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 264:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(4′-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 265:(S)-1-((R)-8-(4′-(azetidin-1-ylmethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 266:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(4′-(morpholinomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 267:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(4′-((2-methoxyethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 268:(S)-1-((R)-8-(4′-((ethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 269:(S)-1-((R)-8-(4′-((cyclobutylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 270:(S)-1-((R)-8-(4′-((2-aminoethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 271:(S)-1-((R)-8-(4′-((3-aminopropylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 272:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(4′-((isobutylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 273:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 274:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-((S)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 275:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 276:2-(3-((S)-3-((R)-8-(1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-2-hydroxypropoxy)phenylsulfonyl)acetamide;Compound 277:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((S)-8-((S)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 278:2-(3-((S)-3-((R)-8-((S)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-2-hydroxypropoxy)phenylsulfonyl)acetamide;Compound 279:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(3-methyl-3H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 280:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one;Compound 281:6-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;Compound 282:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(5,6,7,8-tetrahydroquinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 283:(S)-1-((R)-8-((R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 284:(S)-1-((R)-8-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 285:(S)-1-((R)-8-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 286:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 287:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(3-methyl-3H-imidazo[4,5-b]pyridin-5-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 288:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 289:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 290:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 291:(5)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 292:1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 293:1-ethyl-3-((S)-3-((S)-2-hydroxy-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 294:1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(1-hydroxy-2-methylpropan-2-ylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 295:3-((R)-3-((S)-2-hydroxy-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-methylquinolin-4(1H)-one;Compound 297:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethylquinolin-4(1H)-one;Compound 298:3-((R)-3-((S)-3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethylquinolin-4(1H)-one;Compound 299:1-ethyl-3-((3R)-3-((2S)-3-(3-(1-fluoroethylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 300:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 301:(S)-1-((R)-8-(1-ethoxynaphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 302:(S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(pyrrolo[1,2-a]pyrimidin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 303:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 304:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 305:(S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-((R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 306:1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methoxymethylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 307:(S)-1-((R)-8-(1H-pyrrolo[2,3-b]pyridin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 308:(S)-1-((R)-8-(1H-indol-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 309:(S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 310:1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 311:(S)-1-((R)-8-(1H-indol-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 312:(S)-1-((R)-8-(1H-indol-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methoxymethylsulfonyl)phenoxy)propan-2-ol;Compound 313:5-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one;Compound 314:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethyl-6-fluoroquinolin-4(1H)-one;Compound 315:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethyl-8-methylquinolin-4(1H)-one;Compound 316:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethyl-7-fluoroquinolin-4(1H)-one;Compound 317:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethyl-6-methylquinolin-4(1H)-one;Compound 318:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethyl-7-methylquinolin-4(1H)-one;Compound 319:(S)-1-((R)-8-(1H-pyrazolo[4,3-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol;Compound 320:(S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol;Compound 321:(S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(isopropylsulfonyl)phenoxy)propan-2-ol;Compound 322:1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 323:8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4-ol;Compound 324:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-6-methylquinolin-4-ol;Compound 325:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-6-fluoroquinolin-4-ol;Compound 326:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 327:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-8-methylquinolin-4-ol;Compound 328:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-8-fluoroquinolin-4-ol;Compound 329:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-7-fluoroquinolin-4-ol;Compound 330:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-7-methylquinolin-4-ol;Compound 331:1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 332:1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;Compound 333:3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethyl-8-fluoroquinolin-4(1H)-one;Compound 334:(2S)-1-(4-(methylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 335:(2S)-1-(3-(methylsulfonylmethyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 336:(S)-1-(3-(methylsulfonylmethyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol;Compound 337:1-ethyl-3-((R)-3-((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one;and Compound 338:1-ethyl-3-((S)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one.

Additionally, chemical genera of the present invention and individualcompounds, for example those compounds found in the above list and TableA, including diastereoisomers and enantiomers thereof, encompass allpharmaceutically acceptable salts, solvates, hydrates, and N-oxidesthereof.

The compounds of Formula (Ia) of the present invention may be preparedaccording to relevant published literature procedures that are used byone skilled in the art. Exemplary reagents and procedures for thesereactions appear hereinafter in the working Examples. Protection anddeprotection may be carried out by procedures generally known in the art(see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groupsin Organic Synthesis, 3^(rd) Edition, 1999 [Wiley]).

It is understood that the present invention embraces each isomer, eachdiastereoisomer, each enantiomer and mixtures thereof of each compoundand generic formulae disclosed herein just as if they were eachindividually disclosed with the specific stereochemical designation foreach chiral carbon. Individual isomers and enantiomers can be preparedby selective synthesis, such as, by enantiomeric selective syntheses; orthey can be obtained using separation techniques which are well known topractitioners in the art, such as, by HPLC (including, normal phase,reverse phase, and chiral), recrystallization (i.e., diastereoisomericmixtures) and the like techniques.

Disorders and Methods of Treatment

The compounds disclosed herein are useful in the treatment or preventionof several diseases, disorders, conditions, and/or indications (whichare cumulatively referred to herein as “disorders”). One of skill in theart will recognize that when a disorder, or a method of treatment orprevention, is disclosed herein, such disclosure encompasses secondmedical uses (e.g., a compound for use in the treatment of the disorder,use of a compound for the treatment of the disorder, and use of acompound in the manufacture of a medicament for the treatment of thedisorder).

In some embodiments, the compounds disclosed herein are useful for thetreatment or prevention of a disorder. In some embodiments, thecompounds disclosed herein are useful for the treatment or prevention ofa subtype of a disorder. In some embodiments, the compounds disclosedherein are useful for the treatment or prevention of a symptom of adisorder.

Provided herein are methods for treating or preventing a beta-3adrenergic receptor-mediated disorder. In some embodiments, thecompounds disclosed herein are useful for the prevention of a beta-3adrenergic receptor-mediated disorder. In some embodiments, thecompounds disclosed herein are useful for the treatment or prevention ofa beta-3 adrenergic receptor-mediated disorder.

One aspect of the present invention relates to methods for treating orpreventing a beta-3 adrenergic receptor-mediated disorder in anindividual, comprising administering to the individual in need thereof,a therapeutically effective amount of a compound of the presentinvention; a pharmaceutical product of the present invention; or apharmaceutical composition of the present invention.

One aspect of the present invention relates to methods for treating orpreventing heart failure in an individual, comprising administering tothe individual in need thereof, a therapeutically effective amount of acompound of the present invention; a pharmaceutical product of thepresent invention; or a pharmaceutical composition of the presentinvention.

One aspect of the present invention relates to methods for treating ahypotensive patient or a borderline hypotensive patient, comprisingadministering to the patient in need thereof, a therapeuticallyeffective amount of a compound of the present invention; apharmaceutical product of the present invention; or a pharmaceuticalcomposition of the present invention. One aspect of the presentinvention relates to uses of a compound of the present invention in themanufacture of a medicament for treating or preventing a beta-3adrenergic receptor-mediated disorder in an individual.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating orpreventing heart failure in an individual.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating ahypotensive patient or a borderline hypotensive patient.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating anormotensive patient.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating ahypertensive patient.

One aspect of the present invention relates to uses of a compound of thepresent invention in the manufacture of a medicament for treating apatient following myocardial infarction.

One aspect of the present invention relates to compounds of the presentinvention; a pharmaceutical product of the present invention; or apharmaceutical composition of the present invention; for use in a methodof treatment of the human or animal body by therapy.

One aspect of the present invention relates to compounds of the presentinvention; pharmaceutical products of the present invention; orpharmaceutical compositions of the present invention; for use in amethod for treating or preventing a beta-3 adrenergic receptor-mediateddisorder in an individual.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isselected from the list consisting of: heart failure; reduced cardiacperformance in heart failure; mortality, reinfarction, and/orhospitalization in connection with heart failure; acute heart failure;acute decompensated heart failure; congestive heart failure; severecongestive heart failure; organ damage associated with heart failure(e.g., kidney damage or failure, heart valve problems, heart rhythmproblems, and/or liver damage); heart failure due to left ventriculardysfunction; heart failure with normal ejection fraction; cardiovascularmortality following myocardial infarction; cardiovascular mortality inpatients with left ventricular failure or left ventricular dysfunction;a condition following myocardial infarction; left ventricular failure;left ventricular dysfunction; class II heart failure using the New YorkHeart Association (NYHA) classification system; class III heart failureusing the New York Heart Association (NYHA) classification system; classIV heart failure using the New York Heart Association (NYHA)classification system; LVEF<40% by radionuclide ventriculography; andLVEF≤35% by echocardiography or ventricular contrast angiography.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isheart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isreduced cardiac performance in heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder ismortality, reinfarction, and/or hospitalization in connection with heartfailure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isacute heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isacute decompensated heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder iscongestive heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder issevere congestive heart failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isorgan damage associated with heart failure (e.g., kidney damage orfailure, heart valve problems, heart rhythm problems, and/or liverdamage).

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isheart failure due to left ventricular dysfunction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isheart failure with normal ejection fraction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder iscardiovascular mortality following myocardial infarction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder iscardiovascular mortality in patients with left ventricular failure orleft ventricular dysfunction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isfollowing myocardial infarction.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isleft ventricular failure.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isleft ventricular dysfunction.

Doctors can classify the patient's heart failure according to theseverity of their symptoms. The table below describes the most commonlyused classification system, the New York Heart Association (NYHA)Functional Classification. It places patients in one of four categoriesbased on how much they are limited during physical activity.

Class Patient Symptoms I No limitation of physical activity. Ordinaryphysical activity does not cause undue fatigue, palpitation, dyspnea(shortness of breath). II Slight limitation of physical activity.Comfortable at rest. Ordinary physical activity results in fatigue,palpitation, dyspnea (shortness of breath). III Marked limitation ofphysical activity. Comfortable at rest. Less than ordinary activitycauses fatigue, palpitation, or dyspnea. IV Unable to carry on anyphysical activity without discomfort. Symptoms of heart failure at rest.If any physical activity is undertaken, discomfort increases.

Accordingly, in some embodiments, the beta-3 adrenergicreceptor-mediated disorder is class II heart failure using the New YorkHeart Association (NYHA) classification system.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isclass III heart failure using the New York Heart Association (NYHA)classification system.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isclass IV heart failure using the New York Heart Association (NYHA)classification system.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isLVEF<40% by radionuclide ventriculography.

In some embodiments, the beta-3 adrenergic receptor-mediated disorder isLVEF≤35% by echocardiography or ventricular contrast angiography.

Polymorphs and Pseudopolymorphs

Polymorphism is the ability of a substance to exist as two or morecrystalline phases that have different arrangements and/or conformationsof the molecules in the crystal lattice. Polymorphs show the sameproperties in the liquid or gaseous state but they behave differently inthe solid state.

Besides single-component polymorphs, drugs can also exist as salts andother multicomponent crystalline phases. For example, solvates andhydrates may contain an API host and either solvent or water molecules,respectively, as guests. Analogously, when the guest compound is a solidat room temperature, the resulting form is often called a cocrystal.Salts, solvates, hydrates, and cocrystals may show polymorphism as well.Crystalline phases that share the same API host, but differ with respectto their guests, may be referred to as pseudopolymorphs of one another.

Solvates contain molecules of the solvent of crystallization in adefinite crystal lattice. Solvates, in which the solvent ofcrystallization is water, are termed hydrates. Because water is aconstituent of the atmosphere, hydrates of drugs may be formed rathereasily.

By way of example, Stably published a polymorph screen of 245 compoundsconsisting of a “wide variety of structural types” that revealed about90% of them exhibited multiple solid forms. Overall, approximately halfof the compounds were polymorphic, often having one to three forms.About one-third of the compounds formed hydrates, and about one-thirdformed solvates. Data from cocrystal screens of 64 compounds showed that60% formed cocrystals other than hydrates or solvates. (G. P. Stahly,Crystal Growth & Design (2007), 7(6), 1007-1026).

Isotopes

The present disclosure includes all isotopes of atoms occurring in thecompounds provided herein. Isotopes include those atoms having the sameatomic number but different mass numbers. It is appreciated that certainfeatures of the invention(s) include every combination of one or moreatoms in the compounds provided herein that is replaced with an atomhaving the same atomic number but a different mass number. One suchexample is the replacement of an atom that is the most naturallyabundant isotope, such as ¹H or ¹²C, found in one of the compoundsprovided herein with a different atom that is not the most naturallyabundant isotope, such as ²H or ³H (replacing ¹H), or ¹¹C, ¹³C, or ¹⁴C(replacing ¹²C). A compound wherein such a replacement has taken placeis commonly referred to as being isotopically-labeled. Isotopic-labelingof the present compounds can be accomplished using any one of a varietyof different synthetic methods know to those of ordinary skill in theart and they are readily credited with understanding the syntheticmethods and available reagents needed to conduct such isotopic-labeling.By way of general example, and without limitation, isotopes of hydrogeninclude ²H (deuterium) and ³H (tritium). Isotopes of carbon include ¹¹C,¹³C, and ¹⁴C. Isotopes of nitrogen include ¹³N and ¹⁵N. Isotopes ofoxygen include ¹⁵O, ¹⁷O, and ¹⁸O. An isotope of fluorine includes ¹⁸F.An isotope of sulfur includes ³⁵S. An isotope of chlorine includes ³⁶Cl.Isotopes of bromine include ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, and ⁸²Br. Isotopes ofiodine include ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I. Also provided arecompositions, such as, those prepared during synthesis, preformulation,and the like, and pharmaceutical compositions, such as, those preparedwith the intent of using in a mammal for the treatment of one or more ofthe disorders described herein, comprising one or more of the presentcompounds, wherein the naturally occurring distribution of the isotopesin the composition is perturbed. Also provided herein are compositionsand pharmaceutical compositions comprising compounds of the invention asdescribed herein, wherein the salt is enriched at one or more positionswith an isotope other than the most naturally abundant isotope. Methodsare readily available to measure such isotope perturbations orenrichments, such as, mass spectrometry, and for isotopes that areradio-isotopes additional methods are available, such as,radio-detectors used in connection with HPLC or GC.

One challenge in drug development is improving absorption, distribution,metabolism, excretion, and toxicity (ADMET) properties while maintaininga desired pharmacological profile. Structural changes to improve ADMETproperties often alter the pharmacology of a lead compound. While theeffects of deuterium substitution on ADMET properties are unpredictable,in select cases deuterium can improve a compound's ADMET properties withminimal perturbation of its pharmacology. Two examples where deuteriumhas enabled improvements in therapeutic entities are: CTP-347 andCTP-354. CTP-347 is a deuterated version of paroxetine with a reducedliability for mechanism-based inactivation of CYP2D6 that is observedclinically with paroxetine. CTP-354 is a deuterated version of apromising preclinical gamma-aminobutyric acid A receptor (GABAA)modulator (L-838417) that was not developed due to poor pharmacokinetic(PK) properties. In both cases, deuterium substitution resulted inimproved ADMET profiles that provide the potential for improved safety,efficacy, and/or tolerability without significantly altering thebiochemical potency and selectivity versus the all-hydrogen compounds.Provided are deuterium substituted compounds of the present inventionwith improved ADMET profiles and substantially similar biochemicalpotency and selectivity versus the corresponding all-hydrogen compounds.

Other Utilities

Another object of the present invention relates to radio-labeledcompounds of the present invention that would be useful not only inradio-imaging but also in assays, both in vitro and in vivo, forlocalizing and quantitating beta-3 adrenergic receptors in tissuesamples, including human and for identifying beta-3 adrenergic receptorligands by inhibition binding of a radio-labeled compound. It is afurther object of this invention to develop novel beta-3 adrenergicreceptor assays of which comprise such radio-labeled compounds.

The present disclosure includes all isotopes of atoms occurring in thepresent compounds, intermediates, salts and crystalline forms thereof.Isotopes include those atoms having the same atomic number but differentmass numbers. One aspect of the present invention includes everycombination of one or more atoms in the present compounds,intermediates, salts, and crystalline forms thereof that is replacedwith an atom having the same atomic number but a different mass number.One such example is the replacement of an atom that is the mostnaturally abundant isotope, such as ¹H or ¹²C, found in one the presentcompounds, intermediates, salts, and crystalline forms thereof, with adifferent atom that is not the most naturally abundant isotope, such as²H or ³H (replacing ¹H), or ¹¹C, ¹³C, or ¹⁴C (replacing ¹²C). A compoundwherein such a replacement has taken place is commonly referred to asbeing an isotopically-labeled compound. Isotopic-labeling of the presentcompounds, intermediates, salts, and crystalline forms thereof can beaccomplished using any one of a variety of different synthetic methodsknow to those of ordinary skill in the art and they are readily creditedwith understanding the synthetic methods and available reagents neededto conduct such isotopic-labeling. By way of general example, andwithout limitation, isotopes of hydrogen include ²H (deuterium) and ³H(tritium). Isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C. Isotopes ofnitrogen include ¹³N and ¹⁵N. Isotopes of oxygen include ¹⁵O, ¹⁷O, and¹⁸O. An isotope of fluorine includes ¹⁸F. An isotope of sulfur includes³⁵S. An isotope of chlorine includes ³⁶Cl. Isotopes of bromine include⁷⁵Br, ⁷⁶Br, ⁷⁷Br, and ⁸²Br. Isotopes of iodine include ¹²³I, ¹²⁴I, ¹²⁵I,and ¹³¹I. Another aspect of the present invention includes compositions,such as, those prepared during synthesis, preformulation, and the like,and pharmaceutical compositions, such as, those prepared with the intentof using in a mammal for the treatment of one or more of the disordersdescribed herein, comprising one or more of the present compounds,intermediates, salts, and crystalline forms thereof, wherein thenaturally occurring distribution of the isotopes in the composition isperturbed. Another aspect of the present invention includes compositionsand pharmaceutical compositions comprising compounds as described hereinwherein the compound is enriched at one or more positions with anisotope other than the most naturally abundant isotope. Methods arereadily available to measure such isotope perturbations or enrichments,such as, mass spectrometry, and for isotopes that are radio-isotopesadditional methods are available, such as, radio-detectors used inconnection with HPLC or GC.

Certain isotopically-labeled compounds of the present invention areuseful in compound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Drawings and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or the scarcer radio-isotope or nonradioactiveisotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. Representative synthetic methods for incorporatingactivity levels of tritium into target molecules include, for example:

A. Catalytic Reduction with Tritium Gas: This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]: This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters and the like.

C. Reduction with Lithium Aluminum Hydride [³H]: This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters and the like.

D. Tritium Gas Exposure Labeling: This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]: This procedure is usuallyemployed to prepare O-methyl or N-methyl (³H) products by treatingappropriate precursors with high specific activity methyl iodide (³H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions: This procedure transforms an aryl amineor a heteroaryl amine into a diazonium salt, such as a diazoniumtetrafluoroborate salt and subsequently to ¹²⁵I labeled compound usingNa¹²⁵I. A represented procedure was reported by Zhu, G-D. and co-workersin J. Org. Chem., 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols: This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labelled Compd. Radiopharm., 1999,42, S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I: This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)₄]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresentative procedure was reported by Le Bas, M.-D. and co-workers inJ. Labelled Compd. Radiopharm. 2001, 44, S280-S282.

A radiolabeled beta-3 adrenergic receptor compound of Formula (Ia) canbe used in a screening assay to identify/evaluate compounds. In generalterms, a newly synthesized or identified compound (i.e., test compound)can be evaluated for its ability to reduce binding of the “radiolabeledcompound of Formula (Ia)” to a beta-3 adrenergic receptor. Accordingly,the ability of a test compound to compete with the “radiolabeledcompound of Formula (Ia)” for the binding to a beta-3 adrenergicreceptor directly correlates to its binding affinity.

Certain labeled compounds of the present invention bind to certainbeta-3 adrenergic receptors. In one embodiment the labeled compound hasan IC₅₀ less than about 500 μM, in another embodiment the labeledcompound has an IC₅₀ less than about 100 μM, in yet another embodimentthe labeled compound has an IC₅₀ less than about 10 μM, in yet anotherembodiment the labeled compound has an IC₅₀ less than about 1 μM and instill yet another embodiment the labeled compound has an IC₅₀ less thanabout 0.1 μM.

Compositions and Formulations

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions and syrups. Alternatively, the oral preparations maybe in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound provided herein in a suitable liquid vehicle andfilter sterilizing the solution before filling and sealing anappropriate vial or ampule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20th Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro et. al.).

While it is possible that, for use in the prophylaxis or treatment, acompound provided herein may, in an alternative use, be administered asa raw or pure chemical, it is preferable however to present the compoundor active ingredient as a pharmaceutical formulation or compositionfurther comprising a pharmaceutically acceptable carrier.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with minimal degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds provided herein, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds provided herein or a salt, solvate, or hydrate thereof can beused as active ingredients in pharmaceutical compositions, specificallyas beta-3 adrenergic receptor modulators. The term “active ingredient”,defined in the context of a “pharmaceutical composition”,” refers to acomponent of a pharmaceutical composition that provides the primarypharmacological effect, as opposed to an “inactive ingredient” whichwould generally be recognized as providing no pharmaceutical benefit.

The dose when using the compounds provided herein can vary within widelimits and as is customary and is known to the physician or otherclinician, it is to be tailored to the individual conditions in eachindividual case. It depends, for example, on the nature and severity ofthe illness to be treated, on the condition of the patient, on thecompound employed or on whether an acute or chronic disease state istreated, or prophylaxis conducted, or on whether further activecompounds are administered in addition to the compounds provided herein.Representative doses include, but are not limited to, about 0.001 mg toabout 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg,about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001mg to about 25 mg. Multiple doses may be administered during the day,especially when relatively large amounts are deemed to be needed, forexample 2, 3, or 4 doses. Depending on the individual and as deemedappropriate from the healthcare provider it may be necessary to deviateupward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, on whether anacute or chronic disease state is being treated, or prophylaxisconducted, or on whether further active compounds are administered inaddition to the compounds provided herein and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions provided herein is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods provided herein.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four, or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations.

The daily dose can be divided, especially when relatively large amountsare administered as deemed appropriate, into several, for example two,three, or four-part administrations. If appropriate, depending onindividual behavior, it may be necessary to deviate upward or downwardfrom the daily dose indicated.

The compounds provided herein can be administrated in a wide variety oforal and parenteral dosage forms. It will be obvious to those skilled inthe art that the dosage forms may comprise, as the active component,either a compound provided herein or a pharmaceutically acceptable salt,hydrate, or solvate of a compound provided herein.

For preparing pharmaceutical compositions from the compounds providedherein, the selection of a suitable pharmaceutically acceptable carriercan be either solid, liquid or a mixture of both. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories and dispersible granules. A solid carrier can be one ormore substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is admixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, alow melting wax, cocoa butter and the like. The term “preparation”refers to the formulation of the active compound with encapsulatingmaterial as carrier providing a capsule in which the active component,with or without carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams, or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds provided herein may thus be formulated for parenteraladministration (e.g. by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The pharmaceutical compositions may takesuch forms as suspensions, solutions, or emulsions in oily or aqueousvehicles and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents and thelike.

For topical administration to the epidermis the compounds providedherein may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds providedherein or pharmaceutical compositions comprising them are administeredas aerosols, for example as nasal aerosols or by inhalation, this can becarried out, for example, using a spray, a nebulizer, a pump nebulizer,an inhalation apparatus, a metered inhaler or a dry powder inhaler.Pharmaceutical forms for administration of the compounds provided hereinas an aerosol can be prepared by processes well known to the personskilled in the art. For their preparation, for example, solutions ordispersions of the compounds provided herein in water, water/alcoholmixtures or suitable saline solutions can be employed using customaryadditives, for example benzyl alcohol or other suitable preservatives,absorption enhancers for increasing the bioavailability, solubilizers,dispersants and others and, if appropriate, customary propellants, forexample include carbon dioxide, CFCs, such as, dichlorodifluoromethane,trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The compounds provided herein may optionally exist as pharmaceuticallyacceptable salts including pharmaceutically acceptable acid additionsalts prepared from pharmaceutically acceptable non-toxic acidsincluding inorganic and organic acids. Representative acids include, butare not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic,glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic,pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic,p-toluenesulfonic and the like. Certain compounds provided herein whichcontain a carboxylic acid functional group may optionally exist aspharmaceutically acceptable salts containing non-toxic, pharmaceuticallyacceptable metal cations and cations derived from organic bases.Representative metals include, but are not limited to, aluminium,calcium, lithium, magnesium, potassium, sodium, zinc and the like. Insome embodiments the pharmaceutically acceptable metal is sodium.Representative organic bases include, but are not limited to, benzathine(N¹,N²-dibenzylethane-1,2-diamine), chloroprocaine(2-(diethylamino)ethyl 4-(chloroamino)benzoate), choline,diethanolamine, ethylenediamine, meglumine((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol), procaine(2-(diethylamino)ethyl 4-aminobenzoate), and the like. Certainpharmaceutically acceptable salts are listed in Berge, et. al., Journalof Pharmaceutical Sciences, 66:1-19 (1977).

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds provided herein may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Compounds provided herein can be converted to “pro-drugs.” The term“pro-drugs” refers to compounds that have been modified with specificchemical groups known in the art and when administered into anindividual these groups undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds provided hereincontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Inone general aspect, the “pro-drug” approach is utilized to facilitateoral absorption. A thorough discussion is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S.Symposium Series; and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

Some embodiments include a method of producing a pharmaceuticalcomposition for “combination-therapy” comprising admixing at least onecompound according to any of the compound embodiments disclosed herein,together with at least one known pharmaceutical agent and apharmaceutically acceptable carrier.

It is noted that when the beta-3 adrenergic receptor modulators areutilized as active ingredients in pharmaceutical compositions, these arenot intended for use in humans only, but in non-human mammals as well.Recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as beta-3adrenergic receptor modulators, for the treatment of a beta-3 adrenergicreceptor-associated disease or disorder in companionship animals (e.g.,cats, dogs, etc.) and in livestock animals (e.g., horses, cows, etc.)Those of ordinary skill in the art are readily credited withunderstanding the utility of such compounds in such settings.

Other uses of the disclosed receptors and methods will become apparentto those skilled in the art based upon, inter alia, a review of thisdisclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Example 1 Syntheses of Compounds of the Present Invention

The compounds disclosed herein and their syntheses are furtherillustrated by the following examples. Additional illustrated synthesesfor compounds of the present invention are shown in FIGS. 1 to 24 wherethe symbols have the same definitions as used throughout thisdisclosure. The following examples are provided to further define theinvention without, however, limiting the invention to the particulars ofthese examples. The compounds described herein, supra and infra, arenamed according to the AutoNom version 2.2, CS ChemDraw Ultra Version9.0.7, or ChemBioDraw Ultra 12.0.2.1076. In certain instances commonnames are used and it is understood that these common names would berecognized by those skilled in the art.

Chemistry: Proton nuclear magnetic resonance (¹H NMR) spectra wererecorded on a Bruker Avance III-400 equipped with a 5 mm BBFO probe.Chemical shifts are given in parts per million (ppm) with the residualsolvent signal used as reference. NMR abbreviations are used as follows:s=singlet, d=doublet, dd=doublet of doublets, ddd=doublet of doublet ofdoublets, dddd=doublet of doublet of doublet of doublets, dt=doublet oftriplets, t=triplet, q=quartet, m=multiplet, bs=broad singlet,sxt=sextet. Microwave irradiations were carried out using an Initiator⁺™(Biotage®). Thin-layer chromatography (TLC) was performed on silica gel60 F₂₅₄ (Merck), preparatory thin-layer chromatography (prep TLC) wasperformed on PK6F silica gel 60 Å 1 mm plates (Whatman) and columnchromatography was carried out on a silica gel column using Kieselgel60, 0.063-0.200 mm (Merck). Evaporation was done under reduced pressureon a Blichi rotary evaporator. Celite® 545 was used for filtration ofpalladium.

LCMS spec: HPLC-Agilent 1200; pumps: G1312A; DAD: G1315B; Autosampler:G1367B; Mass spectrometer-Agilent G1956A; ionization source: ESI; DryingGas Flow: 10 L/min; Nebulizer Pressure: 40 psig; Drying Gas Temperature:350° C.; Capillary Voltage: 2500 V) Software: Agilent ChemstationRev.B.04.03.

Example 1.1 Preparation of Benzyl3-((tert-Butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylateStep A: Preparation of Benzyl 4-Allyl-4-hydroxypiperidine-1-carboxylate

To a mixture of benzyl 4-oxopiperidine-1-carboxylate (51 g, 218.6 mmol)in THF (36.44 mL) were added 3-bromoprop-1-ene (54.72 mL, 655.92 mmol)and saturated NH₄Cl (114 mL, 218.6 mmol) aqueous solution. Then Zincdust (31.59 g, 483.1 mmol) was added portion wise while the internalreaction temperature was kept below 40° C. The reaction was stirred atroom temperature overnight. After the reaction was completed, it wasquenched with H₂SO₄ (10%, 225 mL). The reaction mixture was filteredthrough a pad of Celite® and washed with MTBE (1 L). The aqueous layerwas extracted with MTBE (2×) and EtOAc (1×). The combined organic layerswere washed with water and brine, and then dried over MgSO₄, filteredand concentrated to give the title compound (62.39 g, 104% yield). Thismaterial was used in the next step without further purification. LCMSm/z=276.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.55-1.63 (m, 5H), 2.24(d, J=7.33 Hz, 2H), 3.25 (bs, 2H), 3.93 (bs, 2H), 5.14 (s, 2H), 5.21(td, J=9.54, 1.89 Hz, 1H), 5.79-5.93 (m, 1H), 7.33 (dd, J=5.18, 3.41 Hz,1H), 7.35-7.40 (m, 4H).

Step B: Preparation of Benzyl4-(2,3-Dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate

A mixture of K₃Fe(CN)₆ (62.64 g, 190.3 mmol), K₂CO₃ (26.29 g, 190.3mmol), quinuclidine (0.25 g, 2.25 mmol), K₂OsO₂(OH)₄ (0.20 g, 0.53 mmol)was dissolved in H₂O (354.0 mL) and then stirred at room temperature for20 min. (Note: Not all of the salts dissolved in water). A solution ofbenzyl 4-allyl-4-hydroxypiperidine-1-carboxylate (14.72 g, 53.44 mmol)in t-BuOH (354 mL) was prepared then added into the aqueous saltsolution via addition funnel portion wise at room temperature. (Note:All of the salts went into the solution as benzyl4-allyl-4-hydroxypiperidine-1-carboxylate solution was added.) Thenmethanesulfonamide (5.08 g, 53.44 mmol) was added. The reaction mixturechanged color from reddish to green, and was stirred at room temperaturefor 5 h. The reaction was quenched with Na₂SO₃ (51.5 g). The organiclayer was separated and concentrated. The residue was dissolved in EtOAcand extracted with water and brine, then dried over MgSO₄, and filtered.The filtrate was concentrated to give the title compound (19 g, 115%yield) as an oil which was used in the next step without furtherpurification. LCMS m/z=310.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.47(dd, J=14.65, 2.27 Hz, 1H), 1.57 (s, 2H), 1.72 (dd, J=14.65, 11.12 Hz,1H), 1.81 (d, J=12.63 Hz, 1H), 1.88 (t, J=5.43 Hz, 1H), 3.12 (s, 2H),3.16-3.23 (m, 1H), 3.25-3.37 (m, 1H), 3.48 (ddd, J=10.86, 6.95, 5.68 Hz,1H), 3.65 (ddd, J=10.80, 4.61, 3.54 Hz, 1H), 3.92 (bs, 2H), 4.14 (bs,1H), 4.68 (bs, 1H), 5.14 (s, 2H), 7.29-7.40 (m, 5H).

Step C: Preparation of Benzyl3-Hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of benzyl4-(2,3-dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate (17.80 g,57.55 mmol) in CH₂Cl₂ (16 mL) and pyridine (8.90 mL) under nitrogen wereadded N,N-dimethylpyridin-4-amine (1.41 g, 11.51 mmol) and4-methylbenzene-1-sulfonyl chloride (12.07 g, 63.30 mmol) at 0° C. Thereaction was stirred at room temperature overnight. After the reactionwas completed, it was quenched with water and extracted with DCM (5×).The combined organic layers were washed with 1M HCl aqueous solution,water and brine, then dried over MgSO₄ and concentrated. The residue waspurified by silica gel column chromatography to give the title compound(12.5 g, 75% yield) as a yellow oil. LCMS m/z=292.2 [M+H]⁺; ¹H NMR (400MHz, CD₃OD) δ ppm 1.53-1.60 (m, 2H), 1.63-1.72 (m, 1H), 1.79 (ddd,J=13.52, 1.26, 1.14 Hz, 1H), 1.82-1.89 (m, 1H), 1.98 (dd, J=13.52, 6.44Hz, 1H), 3.41 (bs, 2H), 3.67 (dd, J=12.51, 6.44 Hz, 2H), 3.74 (ddd,J=9.60, 2.53, 1.01 Hz, 1H), 3.90 (dd, J=9.60, 4.55 Hz, 1H), 4.39-4.48(m, 1H), 5.11 (s, 2H), 7.26-7.39 (m, 5H).

Step D: Preparation of Benzyl3-Azido-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

Benzyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (10 g, 34.31mmol) was dissolved in pyridine (22 mL) under nitrogen then cooled downto 0° C. Methanesulfonyl chloride (8.76 mL, 113.2 mmol) was added. Thereaction mixture was stirred at room temperature overnight. (Note:Precipitation was formed.). After the reaction was completed, it wasdiluted with EtOAc then washed with H₂O (40 mL), HCl (1N, 30 mL), andbrine (30 mL). The aqueous layers were back extracted with EtOAc (2×).The combined organic layers were dried over MgSO₄, filtered andconcentrated to give benzyl3-((methylsulfonyl)oxy)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate as abrown oil which was used in the next step without further purification.LCMS m/z=370.0 [M+H]⁺.

Benzyl 3-((methylsulfonyl)oxy)-1-oxa-8-azaspiro[4.5]decane-8-carboxylatefrom the previous step was dissolved in DMF (30 mL) under nitrogen.Sodium azide (5.13 g, 78.91 mmol) was added. The reaction was heated at50° C. overnight. After the reaction was cooled down to roomtemperature, it was diluted with EtOAc and washed with water and brine.The aqueous layer was back extracted with EtOAc (2×). The combinedorganic layers were dried over MgSO₄, filtered and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (10.02 g, 92% yield). LCMS m/z=317.2 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 1.56-1.70 (m, 3H), 1.78-1.85 (m, 1H), 1.85-1.91 (m,1H), 2.03 (dd, J=13.64, 7.07 Hz, 1H), 3.29-3.41 (m, 2H), 3.72-3.83 (m,2H), 3.85 (ddd, J=9.98, 3.16, 1.01 Hz, 1H), 3.94-4.00 (m, 1H), 4.15-4.21(m, 1H), 5.14 (s, 2H), 7.29-7.40 (m, 5H).

Step E: Preparation of Benzyl3-((tert-Butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of benzyl3-azido-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (13.11 g, 41.43 mmol)in THF (220 mL) were added acetic acid (16.59 mL, 290.0 mmol) and zincdust (10.84 g, 165.7 mmol). The reaction was heated at 70° C. for 1 h.After the reaction was cooled down to room temperature, it wasneutralized with NaHCO₃ to pH 7. The mixture was passed through a pad ofCelite®, and washed with EtOAc and IPA/DCM (30%). The aqueous layer wasback extracted with EtOAc (3×). (Note: The product was still remained inthe aqueous layer which was then back extracted with IPA/DCM (30%). Thecombined extracts were dried over MgSO₄ and concentrated to give benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, as a white gummysolid which was used in the next step without further purification. LCMSm/z=291.2 [M+H]⁺.

The benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate from theprevious step was dissolved in CH₂Cl₂ (220 mL) followed by addition ofDIEA (14.43 mL, 82.86 mmol) and (BOC)₂O (13.56 g, 62.15 mmol). Thereaction was stirred at room temperature overnight. After the reactionwas completed, the solvent was removed then purified by flash columnchromatography to give the title compound (11.55 g, 71% yield) as awhite solid. LCMS m/z=391.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.44(s, 9H), 1.50-1.54 (m, 1H), 1.58-1.74 (m, 4H), 2.12 (dd, J=13.14, 8.08Hz, 1H), 3.32-3.43 (m, 2H), 3.63 (dd, J=9.09, 5.56 Hz, 1H), 3.67-3.79(m, 2H), 3.99 (dd, J=8.97, 6.19 Hz, 1H), 4.21-4.43 (m, 1H), 4.67-4.70(m, 1H), 5.11 (s, 2H), 7.28-7.39 (m, 5H).

Step F: Chiral HPLC Resolution of Enantiomers of Benzyl3-((tert-Butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

The racemic benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(11.55 g, 29.58 mmol) was resolved to give two enantiomers by normalphase preparative chiral HPLC under the following conditions:

Column: Chiralcel OD, 5 cm×50 cm ID, 20 μm particle size

Eluent: EtOH/Hex (10%) with TEA (0.1%)

Injection: 800 mg/6 mL per injection

Gradient: isocratic

Flow rate: 60 mL/min

Detector: 250 nm

Retention time: 1^(st) enantiomer 28.98 min, 2^(nd) enantiomer 39.38 min

The 1^(st) enantiomer (28.98 min on Chiralcel OD column) and 2^(nd)enantiomer (39.38 min on Chiralcel OD column) was checked by analyticalnormal phase preparative chiral HPLC under the following conditions:

Column: ChiralPak IC, 250×20 mm ID, 5 μm particle size

Eluent: EtOH/Hex (10%) with TEA (0.1%)

Injection: 2 mg/mL per injection

Gradient: isocratic

Flow rate: 1 mL/min

Detector: 250 nm

Retention time of 1^(st) enantiomer (28.97 min on Chiralcel OD) & % ee:31.13 min; 100% ee.

Retention time of 2^(nd) enantiomer (39.382 min on Chiralcel OD) & % ee:28.14 min; 100% ee.

(S)-benzyl 3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1^(st) enantiomer,5.14 g, 45% yield, 100% ee). ¹H NMR (400 MHz, CD₃OD) δ ppm 1.43 (s, 9H),1.49-1.59 (m, 1H), 1.59-1.75 (m, 4H), 2.10 (dd, J=13.14, 8.08 Hz, 1H),3.33-3.46 (m, 2H), 3.58 (dd, J=9.09, 5.56 Hz, 1H), 3.63-3.72 (m, 2H),3.99 (dd, J=9.09, 6.32 Hz, 1H), 4.11-4.20 (m, 1H), 5.11 (s, 2H), 6.86(br.s., 1H), 7.26-7.39 (m, 5H).

(R)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(2^(nd) enantiomer, 4.86 g, 42% yield, 100% ee): ¹H NMR (400 MHz, CD₃OD)δ ppm 1.43 (s, 9H), 1.50-1.58 (m, 1H), 1.60-1.75 (m, 4H), 2.10 (dd,J=13.14, 8.08 Hz, 1H), 3.33-3.46 (m, 2H), 3.58 (dd, J=9.09, 5.56 Hz,1H), 3.63-3.72 (m, 2H), 3.99 (dd, J=9.09, 6.32 Hz, 1H), 4.10-4.20 (m,1H), 5.11 (s, 2H), 6.86 (br.s., 1H), 7.24-7.40 (m, 5H).

The stereochemistry was elucidated using Mosher amide as show in Example1.2 and Example 1.3, respectively.

Example 1.2 Preparation of(S)-3,3,3-Trifluoro-2-methoxy-N—((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-2-phenylpropanamideand(R)-3,3,3-Trifluoro-2-methoxy-N—((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-2-phenylpropanamideStep A: Preparation of One Enantiomer of tert-Butyl(8-(Naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(from 1^(st) Enantiomer)

The 1^(st) enantiomer of benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(1.13 g, 2.89 mmol) from chiral HPLC in Example 1.1 was dissolved inMeOH (10 mL). Palladium/C (30.72 mg, 0.289 mmol) and a H₂ balloon wereapplied. The reaction was stirred at room temperature overnight at roomtemperature. The next day, the H₂ balloon was removed. The reactionmixture was filtered through a pad of Celite®, washed with EtOAc andMeOH, and concentrated to give an enantiomer of tert-butyl1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate (0.64 g, 86% yield) as acolorless gum which was used in the next step without furtherpurification. LCMS m/z=257.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.37 (s, 9H), 1.39-1.42 (m, 2H), 1.46-1.59 (m, 4H), 1.95 (dd, J=12.63,8.34 Hz, 1H), 2.70-2.82 (m, 2H), 3.17 (d, J=2.78 Hz, 1H), 3.40 (dd,J=8.59, 6.57 Hz, 1H), 3.84 (t, J=8.00 Hz, 1H), 3.93-4.10 (m, 1H), 6.99(d, J=5.56 Hz, 1H).

The above obtained enantiomer of tert-butyl1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate (0.64 g, 2.49 mmol) wasdissolved in CH₂Cl₂ (12 mL). DIEA (1.00 mL, 5.77 mmol) was added thenthe resulting mixture was cooled on an ice bath. To the cooled solutionwas added naphthalene-2-sulfonyl chloride (0.92 g, 4.04 mmol). Thereaction was warmed up to room temperature and stirred overnight. Thereaction mixture was concentrated and purified by silica gel columnchromatography to give the title compound (1.12 g, 87% yield) as a whitesolid. LCMS m/z=447.4 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s,9H), 1.52 (dd, J=13.01, 6.44 Hz, 1H), 1.57-1.63 (m, 2H), 1.65-1.73 (m,2H), 1.89 (dd, J=12.88, 8.34 Hz, 1H), 2.62-2.70 (m, 2H), 3.27-3.35 (m,3H), 3.70 (dd, J=8.97, 6.44 Hz, 1H), 3.87-3.99 (m, 1H), 6.93-7.01 (m,1H), 7.66-7.78 (m, 3H), 8.08 (d, J=8.08 Hz, 1H), 8.17 (d, J=8.84 Hz,1H), 8.21 (d, J=7.83 Hz, 1H), 8.42 (d, J=1.52 Hz, 1H).

Step B: Preparation of One Enantiomer of8-(Naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine

To a solution of tert-butyl(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(1.12 g, 2.50 mmol) obtained in Step A above in CH₂Cl₂ (20 mL) at roomtemperature was added 4N HCl (in dioxane, 6.25 mL, 25.01 mmol). Thereaction mixture was stirred at room temperature for 16 h. After thereaction was completed, it was concentrated to give the title compound(1.19 g, 125% yield) as a white solid which was used in the next stepwithout further purification. LCMS m/z=347.0 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.52-1.72 (m, 3H), 1.73-1.90 (m, 2H), 2.06 (dd, J=13.64,8.08 Hz, 1H), 2.53-2.70 (m, 2H), 3.33-3.44 (m, 2H), 3.58 (dd, J=9.60,4.29 Hz, 1H), 3.69-3.82 (m, 2H), 7.64-7.83 (m, 3H), 8.09 (d, J=8.08 Hz,1H), 8.13-8.27 (m, 2H), 8.44 (d, J=1.52 Hz, 1H).

Step C: Preparation of(S)-3,3,3-Trifluoro-2-methoxy-N—((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-2-phenylpropanamide

To a solution of the above obtained8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (10 mg,26.12 μmol) and DIEA (7.54 μL, 43.30 μmol) in THF (1 mL) was added(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (7.92 mg, 31.34μmol) then stirred for 1.5 h. The reaction was quenched with water thenextracted with DCM. The aqueous layer was back extracted with DCM (3×).The combined organics were dried over MgSO₄, filtered and concentrated.The residue was purified by flash column chromatography to give thetitle compound (12 mg, 82% yield) as a white solid. The stereochemistryof the title compound was elucidated by NMR. LCMS m/z=563.4 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm 1.53-1.64 (m, 3H), 1.67-1.76 (m, 2H), 2.07(dd, J=13.52, 7.45 Hz, 1H), 2.79 (qd, J=5.68, 3.41 Hz, 2H), 3.39 (t,J=1.52 Hz, 3H), 3.49 (td, J=11.62, 8.59 Hz, 2H), 3.59 (dd, J=9.73, 3.41Hz, 1H), 3.89 (dd, J=9.73, 5.43 Hz, 1H), 4.42-4.51 (m, 1H), 6.81 (d,J=7.33 Hz, 1H), 7.36-7.43 (m, 3H), 7.46 (d, J=2.27 Hz, 2H), 7.64 (qd,J=7.71, 7.45 Hz, 2H), 7.75 (dd, J=8.59, 1.77 Hz, 1H), 7.93 (d, J=7.83Hz, 1H), 7.98 (d, J=8.34 Hz, 2H), 8.33 (d, J=1.26 Hz, 1H).

Step D: Preparation of(R)-3,3,3-Trifluoro-2-methoxy-N—((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-2-phenylpropanamide

To a solution of the above obtained8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (10 mg,26.12 μmol) and DIEA (6.82 μL, 39.17 μmol) in THF (1 mL) was added(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (7.92 mg, 31.34μmol). The reaction was stirred at room temperature for 1.5 h. It wasquenched with water then extracted with DCM. The aqueous layer was backextracted with DCM (3×). The combined organic layers were dried overMgSO₄, filtered and concentrated. The residue was purified by flashcolumn chromatography to give the title compound (12 mg, 82% yield) as awhite solid. The stereochemistry of the title compound was elucidated byNMR. LCMS m/z=563.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.64-1.80 (m,4H), 1.82-1.92 (m, 1H), 2.13 (dd, J=13.52, 7.45 Hz, 1H), 2.78-2.90 (m,2H), 3.33 (d, J=1.26 Hz, 3H), 3.47-3.60 (m, 3H), 3.88 (dd, J=9.85, 5.56Hz, 1H), 4.48 (dq, J=5.24, 3.81 Hz, 1H), 6.98 (d, J=7.33 Hz, 1H), 7.39(d, J=2.78 Hz, 3H), 7.42-7.48 (m, 2H), 7.64 (qd, J=7.71, 7.45 Hz, 2H),7.76 (dd, J=8.59, 1.77 Hz, 1H), 7.93 (d, J=8.08 Hz, 1H), 7.98 (d, J=8.34Hz, 2H), 8.34 (d, J=1.26 Hz, 1H).

Example 1.3 Preparation of(S)-3,3,3-Trifluoro-2-methoxy-N—((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-2-phenylpropanamideand(R)-3,3,3-Trifluoro-2-methoxy-N—((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-2-phenylpropanamideStep A: Preparation of One Enantiomer of tert-Butyl(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(from 2^(nd) Enantiomer)

The 2^(nd) enantiomer of benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(1.14 g, 2.92 mmol) from chiral HPLC in Example 1.1 was dissolved inMeOH (10 mL). To the resulting solution Palladium/C (31.07 mg, 0.29mmol) and balloon H₂ were applied. The reaction was stirred at roomtemperature for 16 h. The next day, H₂ balloon was removed. The reactionmixture was filtered through a pad of Celite®, washed with EtOAc andMeOH, and concentrated to give an enantiomer of tert-butyl1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate (Peak 2, 735 mg, 98% yield) asa colorless gum which was used in the next step without furtherpurification. LCMS m/z=257.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.34-1.45 (m, 11H), 1.52 (dd, J=6.69, 3.41 Hz, 4H), 1.96 (dd, J=12.63,8.34 Hz, 1H), 2.51-2.59 (m, 2H), 2.71-2.84 (m, 2H), 3.41 (dd, J=8.59,6.57 Hz, 1H), 3.83 (dd, J=8.59, 6.82 Hz, 1H), 3.91-4.07 (m, 1H), 6.99(bs, 1H).

The above obtained enantiomer of tert-butyl1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate was re-dissolved in CH₂Cl₂ (12mL) following by addition of DIEA (1.02 mL, 5.84 mmol). The reaction wascooled in an ice bath then naphthalene-2-sulfonyl chloride (0.93 g, 4.09mmol) was added. The resulting mixture was stirred at room temperatureovernight then concentrated. The residue was purified by silica gelcolumn chromatography to yield the title compound (1.07 g, 82% yield) asa white solid. LCMS m/z=447.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.34 (s, 9H), 1.52 (dd, J=12.88, 6.32 Hz, 1H), 1.56-1.62 (m, 2H),1.65-1.72 (m, 2H), 1.89 (dd, J=12.88, 8.34 Hz, 1H), 2.60-2.71 (m, 2H),3.27-3.35 (m, 3H), 3.70 (dd, J=8.72, 6.44 Hz, 1H), 3.88-3.99 (m, 1H),6.93-7.02 (m, 1H), 7.67-7.78 (m, 3H), 8.08 (d, J=8.34 Hz, 1H), 8.17 (d,J=8.84 Hz, 1H), 8.21 (d, J=8.08 Hz, 1H), 8.42 (d, J=1.26 Hz, 1H).

Step B: Preparation of One Enantiomer of8-(Naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine

To a solution of tert-butyl(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(1.07 g, 2.39 mmol) obtained in Step A above in DCM at room temperaturewas added HCl (4 N in dioxane, 5.97 mL, 23.89 mmol). The reaction wasstirred at room temperature for 16 h. After the reaction was completed,it was concentrated to give the title compound (934 mg, 102% yield) as awhite solid which was used in the next step without furtherpurification. LCMS m/z=347.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.53-1.72 (m, 3H), 1.80 (d, J=3.79 Hz, 2H), 2.01-2.12 (m, 1H), 2.54-2.73(m, 6H), 3.39 (d, J=15.41 Hz, 3H), 3.57 (d, J=5.05 Hz, 1H), 3.76 (d,J=8.84 Hz, 2H), 7.66-7.80 (m, 3H), 8.09 (d, J=8.08 Hz, 1H), 8.17 (d,J=8.84 Hz, 1H), 8.21 (d, J=8.08 Hz, 1H), 8.44 (s, 1H).

Step C: Preparation of(S)-3,3,3-Trifluoro-2-methoxy-N—((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-2-phenylpropanamide

To a solution of the above obtained8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (10 mg,26.12 μmol) and DIEA (7.54 μL, 43.30 μmol) in THF (1 mL) was added(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (7.92 mg, 31.34μmol). The reaction was stirred for 1.5 h at room temperature. Then thereaction was quenched with water and extracted with DCM. The aqueouslayer was back extracted with DCM (3×). The combined organics were driedover MgSO₄, filtered and concentrated. The residue was purified by flashcolumn chromatography to yield the title compound (11 mg, 75% yield) asa white solid. The stereochemistry of the title compound was elucidatedby NMR. LCMS m/z=563.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.65-1.80(m, 4H), 1.82-1.92 (m, 1H), 2.13 (dd, J=13.64, 7.58 Hz, 1H), 2.79-2.89(m, 2H), 3.33 (d, J=1.52 Hz, 3H), 3.48-3.60 (m, 3H), 3.88 (dd, J=9.73,5.43 Hz, 1H), 4.43-4.53 (m, 1H), 6.98 (d, J=7.33 Hz, 1H), 7.37-7.41 (m,3H), 7.43-7.47 (m, 2H), 7.60-7.69 (m, 2H), 7.76 (dd, J=8.72, 1.89 Hz,1H), 7.93 (d, J=7.83 Hz, 1H), 7.98 (d, J=8.34 Hz, 2H), 8.34 (d, J=1.26Hz, 1H).

Step D: Preparation of(R)-3,3,3-Trifluoro-2-methoxy-N—((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)-2-phenylpropanamide

To a solution of the above obtained8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (10 mg,26.12 μmol) and DIEA (7.54 μL, 43.30 μmol) in THF (1 mL) was added(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (7.92 mg, 31.34μmol). The reaction was stirred at room temperature for 1.5 h. Then itwas quenched with water and extracted with DCM. The aqueous was backextracted with DCM (3×). The combined organic layers were dried overMgSO₄, filtered and concentrated. The residue was purified by flashcolumn chromatography to give the title compound (12 mg, 82% yield) as awhite solid. The stereochemistry of the title compound was elucidated byNMR. LCMS m/z=563.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.54-1.66 (m,2H), 1.67-1.79 (m, 3H), 2.06 (dd, J=13.52, 7.45 Hz, 1H), 2.73-2.85 (m,2H), 3.39 (d, J=1.52 Hz, 3H), 3.44-3.55 (m, 2H), 3.59 (dd, J=9.60, 3.54Hz, 1H), 3.89 (dd, J=9.73, 5.43 Hz, 1H), 4.41-4.52 (m, 1H), 6.81 (d,J=7.33 Hz, 1H), 7.37-7.44 (m, 3H), 7.45-7.53 (m, 2H), 7.60-7.71 (m, 2H),7.75 (dd, J=8.59, 1.77 Hz, 1H), 7.93 (d, J=7.83 Hz, 1H), 7.97 (d, J=8.34Hz, 2H), 8.33 (s, 1H).

Example 1.4 Preparation of (R)-Benzyl3-((tert-Butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylateStep A: Preparation of Benzyl 4-Allyl-4-hydroxypiperidine-1-carboxylate

To an ice-cooled mixture of benzyl 4-oxopiperidine-1-carboxylate (900.00g, 3.86 mol), 3-bromoprop-1-ene (1.17 kg, 9.65 mol) and NH₄Cl (3.30 L)in THF (750.00 mL) was added Zn (630.74 g, 9.65 mol) portion wise at5-10° C. After the addition, the mixture was kept at 30° C. for 3 h.After benzyl 4-oxopiperidine-1-carboxylate was consumed, the mixture wasfiltered. The filtrate was extracted with ethyl acetate (2 L×3). Thecombined organic layer was washed with brine (1 L×2), dried overanhydrous Na₂SO₄, and concentrated to give the title compound (1.02 kg,crude) as a yellow oil which was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.45-1.75 (m, 4H), 2.22 (d,J=4.0 Hz, 2H), 3.23 (bs, 1H), 3.92 (bs, 2H), 5.05-5.25 (m, 4H),5.75-5.95 (m, 1H), 7.25-7.45 (m, 5H).

Step B: Preparation of Benzyl4-(2,3-Dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate

To a solution of benzyl 4-allyl-4-hydroxypiperidine-1-carboxylate (1.16kg, 4.21 mol) in THF (2.20 L), acetone (2.20 L) and H₂O (2.20 L) wereadded K₂OsO₄.2H₂O (7.76 g, 21.05 mmol) and NMO (1.04 kg, 8.84 mol,933.08 mL). Then the reaction was stirred at 30° C. for 12 h. Themixture was diluted with saturated Na₂SO₃ aqueous solution (5 L) andextracted with ethyl acetate (2 L×2). The combined organics were washedwith brine (2 L), dried over Na₂SO₄, filtered and concentrated to givethe title compound as an off-white solid without further purification(1.10 kg, 83.14% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.60 (m,6H), 3.00-3.30 (m, 4H), 3.65-3.86 (m, 3H), 4.52-4.62 (m, 2H), 4.67-4.74(m, 1H), 5.06 (s, 2H), 7.28-7.42 (m, 5H).

Step C: Preparation of Benzyl3-((Methylsulfonyl)oxy)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of benzyl4-(2,3-dihydroxypropyl)-4-hydroxypiperidine-1-carboxylate (1.34 kg, 4.33mol), DMAP (158.75 g, 1.30 mol) and pyridine (1.03 kg, 12.99 mol, 1.05L) in DCM (5.36 L) was added MsCl (1.13 kg, 9.86 mol, 763.51 mL) at 0°C. The reaction was stirred at 25° C. for 3 hrs. Then the reactionmixture was heated and stirred at 40° C. for 12 h. Then the mixture wasadded additional MsCl (319.00 g, 2.78 mol, 215.54 mL) at 25° C. and theresulting mixture was stirred at 40° C. for 24 h. The mixture wasdiluted with DCM (5 L), washed with 1 N HCl (4 L) and brine (4 L) insequence. The organic phase was dried over Na₂SO₄ and filtered. Thefiltrate was concentrated to give the title compound (1.55 kg) as brownoil, which was used directly for the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38-1.75 (m, 6H),1.96-2.20 (m, 2H), 3.12-3.41 (m, 5H), 3.50-3.67 (m, 2H), 3.94-3.95 (m,2H), 5.06 (s, 2H), 5.29 (s, 1H), 7.25-7.44 (m, 5H).

Step D: Preparation of Benzyl3-Amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of benzyl3-((methylsulfonyl)oxy)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(300.00 g, 812.06 mmol) in DMF (1.50 L) was added NaN₃ (61.00 g, 938.32mmol, 32.97 mL) in H₂O (150.00 mL) and the resultant mixture was stirredat 70° C. for 16 h. PPh₃ (425.99 g, 1.62 mol, 2.00 eq) was added portionwise at 70° C. (Caution: gas generated). The mixture was stirred at 70°C. for another 2 h. After cooled to 15° C., water (6 L) was added andthe mixture was basified to pH=10 with Na₂CO₃. The mixture was extractedwith ethyl acetate (3 L×3) and the combined organics layers were washedwith 1 N HCl (3 L×3). The combined aqueous phase was basified to pH=10with NaOH, extracted with ethyl acetate (3 L×3). The combined organicswere washed with brine (3 L), dried over Na₂SO₄, filtered andconcentrated to give the title compound (153.00 g, 58.4% yield). ¹H NMR(400 MHz, CDCl₃) δ ppm 1.37 (s, 1H), 1.42-1.85 (m, 5H), 2.05 (dd, J=12.8Hz, 5.4 Hz, 1H), 3.25-3.45 (m, 2H), 3.45-3.56 (m, 1H), 3.57-3.80 (m,3H), 3.93 (dd, J=6.4 Hz, 5.7 Hz, 1H), 5.11 (s, 2H), 7.24-7.42 (m, 5H).

Step E: Preparation of (R)-Benzyl3-Amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (126 g, 434 mmol, 1.0eq) in MeOH (2.5 L) was added di-p-toluoyl-D-tartaric acid (37 g, 95.5mmol, 0.44 eq) and the mixture was heated to 78° C. After stirred atthis temperature for 5 h, the mixture was cooled to 25° C. slowly andstirred at this temperature for 1 h. The white solid was collected byfiltration and the solid was washed with MeOH (500 mL). The filter cakewas added to NaHCO₃ aqueous solution (500 mL) and extracted with DCM (1L×2). The combined organics were washed with brine, dried over Na₂SO₄,filtered and concentrated to give the title compound (54 g) which wasanalyzed by supercritical fluid chromatography (SFC) (AD-3S_4_25_3ML;Column: Chiralpak AD-3 100×4.6 mm I.D., 3 μm; Mobile phase: 25%isopropanol (0.05% DEA) in CO₂; Flow rate: 3 mL/min; Wavelength: 220 nm)to have ee value of 93%. The above material (42 g, 145 mmol, 1.0 eq) wasdissolved with MeOH (800 mL), followed by the addition ofdi-p-toluoyl-D-tartaric acid (27 g, 69 mmol, 0.96 eq). The mixture washeated to 78° C. After stirred at this temperature for 5 h, the mixturewas cooled to 25° C. slowly and stirred at this temperature for 1 h. Thewhite solid was collected by filtration, washed with EtOH (500 mL). Thecake was added to NaHCO₃ aqueous (500 mL) and extracted with DCM (1L×2). The combined organics were washed with brine, dried over Na₂SO₄,filtered and concentrated to give the title compound (36 g, 97.5% ee) ascolorless oil.

Step F: Preparation of (R)-Benzyl3-((tert-Butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (36 g, 124 mmol, 1.0eq) in DCM (600 mL) were added TEA (25 g, 248 mmol, 2.0 eq) and Boc₂O(30 g, 136 mmol, 1.1 eq). The reaction was stirred at 20° C. for 6 h.The mixture was washed with cold HCl aqueous solution (1N, 200 mL) andbrine, dried over Na₂SO₄, filtered and concentrated. The residue wastriturated with petroleum ether to give the title compound (44 g, 91%yield) as a white solid. LCMS m/z=335.1 (M-tBu+H); ¹H NMR (400 MHz,DMSO-d₆) δ 1.38 (s, 9H), 1.44-1.64 (m, 5H), 1.95-2.05 (m, 1H), 3.39-3.36(m, 2H), 3.53-3.55 (m, 3H), 3.89 (t, J=6.4 Hz, 1H), 4.01-4.10 (m, 1H),5.06 (s, 2H), 7.10 (d, J=6.0 Hz, 1H), 7.38-7.32 (m, 5H).

SFC analysis: (AD-3S_5_40_3ML; Column: Chiralpak AD-3 100×4.6 mm I.D., 3μm; Mobile phase: 40% ethanol (0.05% DEA) in CO₂; Flow rate: 3 mL/min;Wave length: 220 nm) 100% ee.

Example 1.5 Preparation of (S)-Benzyl3-((tert-Butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylateStep A: Preparation of (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (97 g, 0.334 mol, 1.0eq) in MeOH (2.5 L) was added di-p-toluoyl-L-tartaric acid (40 g, 104mmol, 0.62 eq) and the mixture was heated to 78° C. After stirred atthis temperature for 5 h, the mixture was cooled to 25° C. slowly andstirred at this temperature for 1 h. The white solid was collected byfiltration and the solid was washed with MeOH (250 mL). The filter cakewas added to NaHCO₃ aqueous solution (300 mL) and extracted with DCM(500 mL×2). The combined organics were washed with brine, dried overNa₂SO₄, filtered and concentrated to give the residue (45 g) which wasanalyzed by SFC (AD-3S_4_25_3ML; Column: Chiralpak AD-3 100×4.6 mm I.D.,3 μm; Mobile phase: 25% isopropanol (0.05% DEA) in CO₂; Flow rate: 3mL/min, wavelength: 220 nm) to have ee value of 95%. The above material(45 g, 150 mmol, 1.0 eq) was dissolved with MeOH (1.2 L), followed bythe addition of di-p-toluoyl-L-tartaric acid (28 g, 72 mmol, 0.96 eq.)and the mixture was heated to 78° C. After stirred at this temperaturefor 5 h, the mixture was cooled to 25° C. slowly and stirred at thistemperature for 1 h. The white solid was collected by filtration, washedwith EtOH (500 mL). The cake was added to NaHCO₃ aqueous solution (300mL) and extracted with DCM (500 mL×2). The combined organics were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give thetitle compound (40 g, 97.5% ee) as a colorless oil.

Step B: Preparation of (S)-Benzyl3-((tert-Butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (40 g, 138 mmol, 1.0eq) in DCM (600 mL) were added TEA (28 g, 276 mmol, 2.0 eq) and Boc₂O(33 g, 152 mmol, 1.1 eq). The reaction was stirred at 20° C. for 6 h.The mixture was washed with cold HCl aq. (1 N, 200 mL) and brine, driedover Na₂SO₄, filtered and concentrated. The residue was triturated withpetroleum ether to give the title compound (51 g, 131 mmol, 95% yield)as a white solid. LCMS m/z=335.1 (M-tBu+H); ¹H NMR (400 MHz DMSO-d₆) δ1.38 (s, 9H), 1.48-1.62 (m, 5H), 1.96-2.07 (m, 1H), 3.19-3.36 (m, 2H),3.53-3.43 (m, 3H), 3.89 (t, J=6.4 Hz, 1H), 4.04-4.11 (m, 1H), 5.06 (s,2H), 7.10-7.09 (d, J=6.0 Hz, 1H), 7.38-7.32 (m, 5H).

SFC analysis: (AD-3S_5_40_3ML; Column: Chiralpak AD-3 100×4.6 mm I.D., 3μm; Mobile phase: 40% ethanol (0.05% DEA) in CO₂; Flow rate: 3 mL/min;Wave length: 220 nm) 100% ee.

Example 1.6 Preparation of(S)-2-((3-((Cyclopropylmethyl)sulfonyl)phenoxy)methyl)oxirane (MethodBB1) Step A: Preparation of Sodium 3-Methoxybenzenesulfinate (MethodBB1A)

To a solution of sodium sulfite (3.56 g, 28.26 mmol) and sodiumcarbonate (3 g, 28.26 mmol) in H₂O (18.84 mL) was added3-methoxybenzene-1-sulfonyl chloride (2 mL, 14.13 mmol) and EtOH (9.42mL). The reaction was heated at 60° C. for 3 h. The mixture wasconcentrated and azeotroped with toluene (2×) to give the title compoundas a light yellow solid which was used in the next step without furtherpurification. LCMS m/z=170.8 [M−H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.75 (s, 3H), 6.77 (d, J=1.01 Hz, 1H), 6.99-7.06 (m, 2H), 7.20 (t,J=7.71 Hz, 1H).

Step B: Preparation of 1-((Cyclopropylmethyl)sulfonyl)-3-methoxybenzene(Method BB1B)

To a solution of sodium 3-methoxybenzenesulfinate (300 mg, 1.55 mmol) inDMF (6.0 mL) was added (bromomethyl)cyclopropane (0.63 g, 1.55 mmol).The reaction was heated under microwave irradiation for 1.5 h at 120° C.Then it was filtered through a pad of Celite®, washed with EtOAc andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (289 mg, 83% yield). LCMSm/z=227.0 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 0.17 (q, J=5.31 Hz, 2H),0.59 (td, J=7.20, 5.05 Hz, 2H), 1.02 (tt, J=8.08, 4.80 Hz, 1H), 3.03 (d,J=7.07 Hz, 2H), 3.88 (s, 3H), 7.18 (ddd, J=8.15, 2.59, 1.14 Hz, 1H),7.44-7.50 (m, 2H), 7.53 (dt, J=8.00, 1.39 Hz, 1H).

Step C: Preparation of 3-((Cyclopropylmethyl)sulfonyl)phenol (MethodBB1C)

To a solution of 1-((cyclopropylmethyl)sulfonyl)-3-methoxybenzene (290mg, 1.28 mmol) in DCM (6.4 mL) at −20° C. under nitrogen, borontribromide (176 μl, 2.56 mmol) in DCM (2.6 mL) was added drop wise. Thereaction mixture was stirred at room temperature overnight. After thereaction was completed, it was cooled down to −20° C. then quenched withMeOH and neutralized with 7N NH₃ in MeOH. The resulting mixture wasfiltered through a pad of Celite® to remove NH₄Br salt; the organiclayer was washed with water and brine, then dried over Na₂SO₄, filteredand concentrated. The residue was purified by silica gel columnchromatography to give the title compound (229 mg, 72% yield). LCMSm/z=212.8 [M]⁺; NMR (400 MHz, CDCl₃) δ ppm 0.12-0.24 (m, 2H), 0.52-0.65(m, 2H), 0.95-1.07 (m, 1H), 3.05 (d, J=7.33 Hz, 2H), 6.12 (s, 1H), 7.15(ddd, J=7.83, 2.40, 1.39 Hz, 1H), 7.44 (t, J=8.08 Hz, 1H), 7.47-7.52 (m,2H).

Step D: Preparation of(S)-2-((3-((Cyclopropylmethyl)sulfonyl)phenoxy)methyl)oxirane. (MethodBB1D)

In a 5 mL microwave vial were added3-((cyclopropylmethyl)sulfonyl)phenol (100 mg, 0.47 mmol), potassiumcarbonate (195 mg, 1.41 mmol) and acetone (2 mL). The reaction wasstirred at room temperature for 10 min then (S)-oxiran-2-ylmethyl3-nitrobenzenesulfonate (122 mg, 0.47 mmol) was added. The reaction washeated at 70° C. overnight. After cooling down to room temperature, themixture was filtered through a pad of Celite®, washed with EtOAc andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (121 mg, 87% yield) as acolorless oil. LCMS m/z=269.0 [M+H]⁺.

Example 1.7 Preparation of(S)-2-((3-(Oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol. (Method BB2) StepA: Preparation of 3-((2-Hydroxyethyl)thio)phenol

To a solution of 3-mercaptophenol (14.6 g, 115.7 mmol) in DCM (400 mL)containing DIEA (40.31 mL, 231.4 mmol) at 0° C. under nitrogen was addeda solution of 2-bromoethanol (17.35 g, 138.9 mmol) in DCM (75 mL) viaadditional funnel. The reaction was stirred at room temperatureovernight. After the reaction was completed, it was neutralized with HCl(0.5N) aqueous solution to pH 6 then the organic layer was separated.The aqueous layer was back extracted with DCM. The combined organiclayers were washed with brine, then dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (21.65 g, 62% yield). LCMSm/z=171.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.97 (t, J=6.95 Hz,2H), 3.51-3.58 (m, 2H), 4.91 (t, J=5.56 Hz, 1H), 6.57 (ddd, J=8.72,1.39, 1.26 Hz, 1H), 6.70-6.75 (m, 2H), 7.09 (t, J=8.08 Hz, 1H), 9.49 (s,1H).

Step B: Preparation of 3-((2-Hydroxyethyl)sulfonyl)phenol

To a solution of 3-((2-hydroxyethyl)thio)phenol (21.65 g, 78.9 mmol) inMeOH (217.5 mL) and H₂O (54.38 mL) at 0° C. was added potassiumperoxymonosulfate, Oxone® (72.95 g, 157.7 mmol) portion wise. Thereaction mixture was stirred at room temperature overnight. It wasfiltered through a pad of Celite®, washed with MeOH, and concentrated.The residue was diluted in water then adjust pH to pH 8-9 using NaHCO₃.The aqueous solution was extracted with DCM. The combined organic layerswere washed with water (1×) and brine (1×), then dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gel columnchromatography to give the title compound (14.02 g, 88% yield) as ayellow solid. LCMS m/z=203.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm3.39 (t, J=6.44 Hz, 2H), 3.61-3.70 (m, 2H), 4.87 (t, J=5.43 Hz, 1H),7.09 (ddd, J=8.15, 2.46, 1.01 Hz, 1H), 7.23 (d, J=2.27 Hz, 1H), 7.30(dd, J=8.97, 1.39 Hz, 1H), 7.44 (t, J=7.96 Hz, 1H), 10.19 (s, 1H).

Step C: Preparation of(S)-2-((3-(Oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol

To a mixture of 3-((2-hydroxyethyl)sulfonyl)phenol (14.02 g, 45.76 mmol)and potassium carbonate (18.97 g, 137.3 mmol) in acetone (91.51 mL)under nitrogen was added (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate(11.86 g, 45.76 mmol) at room temperature. The reaction was heated at80° C. overnight. After the reaction was cooled down to roomtemperature, the mixture was filtered through a pad of Celite®, washedwith acetone then concentrated. The residue was re-dissolved in EtOAcand washed with aqueous NaOH (1N) solution, water and brine. The aqueouslayer was back extracted with EtOAc (2×). The combined organic layerswere washed with water and brine, then dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (15.23 g, 85% yield). LCMSm/z=259.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.74 (dd, J=5.05, 2.53Hz, 1H), 2.86 (t, J=4.29 Hz, 1H), 3.33-3.38 (m, 1H), 3.46 (t, J=6.44 Hz,2H), 3.63-3.70 (m, 2H), 3.94 (dd, J=11.37, 6.57 Hz, 1H), 4.46 (dd,J=11.37, 2.53 Hz, 1H), 4.87 (t, J=5.56 Hz, 1H), 7.32 (dt, J=8.27, 1.29Hz, 1H), 7.42 (d, J=2.27 Hz, 1H), 7.46-7.49 (m, 1H), 7.56 (t, J=7.96 Hz,1H).

Example 1.8 Preparation of(S)-2-((3-(Methylsulfonyl)phenoxy)methyl)oxirane (Method BB3) Step A:Preparation of 3-(Methylsulfonyl)phenol (Method BB3A)

To a solution of 1-methoxy-3-(methylsulfonyl)benzene (2.58 g, 13.86mmol) in CH₂Cl₂ (12 mL) at below −20° C. was added slowly a solution ofboron tribromide (2.63 mL, 27.72 mmol) under nitrogen. The reactionchanged color from pale yellow to red color. The reaction was slowlywarmed up to room temperature overnight. After the reaction wascompleted, the mixture was cooled down to −20° C., then quenched withMeOH, and then diluted with CH₂Cl₂. The reaction mixture was neutralizedwith NaHCO₃ by slowly adding into the saturated NaHCO₃ aqueous solutionfollowed by addition of NaHCO₃ solid. The organic layer was separatedand the aqueous layer was back extracted with CH₂Cl₂. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (2.46 g, 103% yield) as a white solid. LCMS m/z=173.2[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.09 (s, 3H), 7.15 (ddd, J=7.83,2.53, 1.52 Hz, 1H), 7.41-7.53 (m, 3H).

Step B: Preparation of (S)-2-((3-(Methylsulfonyl)phenoxy)methyl)oxirane

To a solution of 3-(methylsulfonyl)phenol (2.46 g, 14.29 mmol) inacetone (70 mL) was added potassium carbonate (3.95 g, 28.57 mmol). Thereaction was stirred at room temperature for 10 min. Then(S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (3.70 g, 14.29 mmol) wasadded. The reaction was heated at 70° C. overnight under nitrogen. Aftercooling down to room temperature, the mixture was filtered through a padof Celite®, washed with acetone, and concentrated. The residue waspurified by silica gel column chromatography to give the title compound(3.03 g, 93% yield) as a colorless oil. LCMS m/z=229.4 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 2.79 (dd, J=4.80, 2.78 Hz, 1H), 2.94 (t, J=4 Hz,1H), 3.06 (s, 3H), 3.33-3.42 (m, 1H), 3.99 (dd, J=11.12, 6.06 Hz, 1H),4.37 (dd, J=11.12, 2.78 Hz, 1H), 7.22 (ddd, J=8.21, 2.65, 1.01 Hz, 1H),7.46-7.52 (m, 2H), 7.54-7.58 (m, 1H).

Example 1.9 Preparation of(S)-2-((3-(Cyclopropylsulfonyl)phenoxy)methyl)oxirane (Method BB4) StepA: Preparation of 3-(Cyclopropylthio)phenol

To a stirred suspension of potassium tert-butoxide (8.00 g, 71.33 mmol)in DMSO (70 mL) under nitrogen was added 3-mercaptophenol (5 g, 39.63mmol) at 0° C.; the reaction was stirred at room temperature for 30 min.Then bromocyclopropane (5.72 mL, 71.33 mmol) was added into the reactionmixture. The reaction was heated at 90° C. overnight. After the reactionwas completed, it was diluted with EtOAc. The organic layer was washedwith water, saturated NH₄Cl aqueous solution (2×), and brine. Theaqueous layer was back extracted with EtOAc (1×). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated. The residuewas purified by silica gel column chromatography to give the titlecompound (6.19 g, 85% yield). LCMS m/z=167.2 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 0.68-0.74 (m, 2H), 1.05-1.12 (m, 2H), 2.13-2.22 (m, 1H),4.75 (s, 1H), 6.60 (dt, J=8.08, 1.26 Hz, 1H), 6.89 (t, J=2.27 Hz, 1H),6.93 (ddd, J=7.83, 1.64, 0.88 Hz, 1H), 7.15 (t, J=7.96 Hz, 1H).

Step B: Preparation of(S)-2-((3-(Cyclopropylsulfonyl)phenoxy)methyl)oxirane

To a round bottom flask containing Al₂O₃ (56 g) was added water (71 mL).To this mixture a solution of 3-(cyclopropylthio)phenol (6.19 g, 33.60mmol) in CCl₄ (170 mL) was added followed by addition of potassiumperoxymonosulfate (Oxone®) (31.09 g, 67.21 mmol). The reaction washeated at 40° C. for 8 h; then the reaction was stirred at roomtemperature overnight. After the reaction was completed, the mixture wasfiltered through a pad of Celite® and washed with CH₂Cl₂. The organiclayer was washed with water and brine, then dried over Na₂SO₄, filteredand concentrated to give 3-(cyclopropylsulfonyl)phenol (7.07 g, 106%yield) as a solid. This material was used in the next step withoutfurther purification. LCMS m/z=199.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δppm 1.02-1.10 (m, 2H), 1.33-1.39 (m, 2H), 2.49 (tt, J=8.05, 4.83 Hz,1H), 6.18 (bs, 1H), 7.13 (dt, J=6.51, 2.56 Hz, 1H), 7.40-7.48 (m, 3H).

To a solution of 3-(cyclopropylsulfonyl)phenol in acetone (170.0 mL) wasadded potassium carbonate (9.29 g, 67.21 mmol) and (S)-oxiran-2-ylmethyl3-nitrobenzenesulfonate (8.71 g, 33.60 mmol). The reaction was heated at70° C. overnight under nitrogen. After the reaction was completed, themixture was filtered through a pad of Celite®, washed with acetone andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (7.63 g, 89% yield) as a lightyellow oil. LCMS m/z=255.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm1.01-1.08 (m, 2H), 1.33-1.39 (m, 2H), 2.47 (tt, J=7.99, 4.89 Hz, 1H),2.79 (dd, J=4.80, 2.53 Hz, 1H), 2.93 (t, J=4.29 Hz, 1H), 3.35-3.41 (m,1H), 3.99 (dd, J=11.12, 5.81 Hz, 1H), 4.36 (dd, J=11.12, 2.78 Hz, 1H),7.20 (ddd, J=8.02, 2.59, 1.26 Hz, 1H), 7.44 (t, J=2.27 Hz, 1H), 7.47 (t,J=7.71 Hz, 1H), 7.50-7.54 (m, 1H).

Example 1.10 Preparation of(S)-2-((3-(Oxiran-2-ylmethoxy)phenyl)sulfonyl)acetamide (Method BB5)Step A: Preparation of 2-((3-Hydroxyphenyl)thio)acetamide (Method BB5A)

To a solution of sodium hydroxide (4.82 g, 123.6 mmol) in MeOH (120 mL)at 0° C. was added a solution of 3-mercaptophenol (10.51 mL, 103.0 mmol)in MeOH (20 mL). The reaction was warmed up to room temperature thenstirred for 30 min. A solution of 2-bromoacetamide (31.28 g, 226.6 mmol)in MeOH (100 mL) was added into the reaction mixture. The reaction wasstirred at room temperature overnight. After the reaction was completed,the mixture was filtered through a pad of Celite® then washed with MeOH.The filtrate was concentrated then the residue was re-dissolved in waterand extracted with IPA/DCM (10%, 2×). The combined organic layers werewashed with water and brine, then dried over Na₂SO₄, filtered andconcentrated. The residue was triturated with DCM/Hex (2:1 ratio) togive the title compound (17.19 g, 96% yield) as a light brown solid.LCMS m/z=184.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 3.59 (s, 2H), 6.64(ddd, J=8.15, 2.34, 0.88 Hz, 1H), 6.80-6.86 (m, 2H), 7.11 (t, J=7.83 Hz,1H).

Step B: Preparation of 2-((3-Hydroxyphenyl)sulfonyl)acetamide (MethodBB5B)

To a solution of 2-((3-hydroxyphenyl)thio)acetamide (18.04 g, 98.46mmol) in MeOH (272 mL) and H₂O (68 mL) at 0° C. was added a solution ofpotassium peroxymonosulfate (Oxone®) (91.09 g, 196.9 mmol) portion wise.The reaction was stirred at room temperature overnight. The reactionmixture was filtered through a pad of Celite®, washed with MeOH and thenconcentrated. The residue was dissolved in water and neutralized withsaturated NaHCO₃ aqueous to pH 8. (Note: The aqueous layer changed colorto light pink.) The aqueous layer was extracted with IPA/DCM (10%). Theorganic layer was washed with water and brine, dried over Na₂SO₄,filtered and concentrate to give the title compound (15.11 g, 71% yield)as a white solid. LCMS m/z=216.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm4.10 (s, 2H), 7.11 (ddd, J=7.83, 2.53, 1.26 Hz, 1H), 7.33 (t, J=2.02 Hz,1H), 7.39 (t, J=1.52 Hz, 1H), 7.42 (t, J=7.58 Hz, 1H).

Step C: Preparation of(S)-2-((3-(Oxiran-2-ylmethoxy)phenyl)sulfonyl)acetamide

To a solution of 2-((3-hydroxyphenyl)sulfonyl)acetamide (24.35 g, 70.2mmol) in acetone (351 mL) was added potassium carbonate (19.39 g, 140.3mmol) and (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (28.5 g, 104.4mmol). The reaction was heated at 80° C. for 23 h. After cooling down toroom temperature, the reaction mixture was filtered through a pad ofCelite®, washed with Acetone, and then concentrated. The residue waspurified by silica gel column chromatography to give the title compound(13.9 g, 73% yield) as a light yellow solid. LCMS m/z=272.0 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm 2.78 (dd, J=4.80, 2.78 Hz, 1H), 2.94 (t,J=4.04 Hz, 1H), 3.38 (dddd, J=6.13, 3.85, 2.91, 2.78 Hz, 1H), 3.96-4.04(m, 3H), 4.36 (dd, J=11.12, 2.78 Hz, 1H), 5.61 (bs, 1H), 6.72 (bs, 1H),7.24-7.29 (m, 1H), 7.47 (t, J=1.77 Hz, 1H), 7.52 (t, J=7.83 Hz, 1H),7.54 (dt, J=7.83, 1.52 Hz, 1H).

Example 1.11 Preparation of(S)-(1-((3-(Oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl) methanol(Method BB6) Step A: Preparation of 3-((3-Chloropropyl)thio)phenol

To a solution of 3-mercaptophenol (4.5 g, 35.66 mmol) in CH₂Cl₂ (60 mL,0.6M) was added triethylamine (9.94 mL, 71.33 mmol) at 0° C. withvigorous stirring. The resulting suspension was added1-bromo-3-chloropropane (6.74 g, 42.80 mmol) drop wise at 0° C. Thereaction was stirred at room temperature for 1 h. The mixture was addedDCM (100 mL) and water (60 mL). The organic layer was separated, and theaqueous layer was extracted with DCM (2×). The organic extracts werecombined and washed with water (2×), brine, dried over Na₂SO₄, andfiltered. The filtrate was concentrated to give the title compound as athick yellowish liquid without further purification.

Step B: Preparation of 3-((3-Chloropropyl)sulfonyl)phenol

The crude 3-((3-chloropropyl)thio)phenol from Step A above was dissolvedin dioxane and water (4:1, 100 mL). To this solution was added Oxone®(65.78 g, 107.0 mmol) portion wise. The white suspension was stirred atroom temperature for 1 h. The white solid was filtered and washed withEtOAc (50 mL). The filtrate was concentrated under reduced pressure toremove the organic solvents. The resulting aqueous solution wasextracted with EtOAc (3×75 mL). The combined organic extracts werewashed with saturated aqueous NaHCO₃ solution, brine, dried over Na₂SO₄and filtered. The filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound (7.77 g,89.7% yield). LCMS m/z=235.2 [M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm2.18-2.25 (m, 2H), 3.27-3.31 (m, 2H), 3.61 (t, J=6.20 Hz, 2H), 7.14-7.19(m, 1H), 7.43-7.47 (m, 3H).

Step C: Preparation of 3-(Cyclopropylsulfonyl)phenol

To a solution of 3-((3-chloropropyl)sulfonyl)phenol (5.0 g, 21.30 mmol)in THF (150 mL) was added drop wise potassium bis(trimethylsilyl)amide(1.0 M in MTBE, 46.87 mL, 46.87 mmol) at −78° C., which resultedformation of a thick suspension. The reaction was vigorously stirred for30 min, then warmed up to room temperature overnight. The mixture wasquenched with 2N HCl (50 mL) and the aqueous layer was extracted with 5%of MeOH/EtOAc (3×). The combined organic extract was washed with brine,dried over Na₂SO₄, and filtered. The filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (3.6 g, 85.2% yield) as a light yellow solid. LCMSm/z=199.4 [M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 1.03-1.09 (m, 2H),1.33-1.38 (m, 2H), 2.45-2.52 (m, 1H), 6.44 (s, 1H), 7.10-7.15 (m, 1H),7.40-7.46 (m, 3H).

Step D: Preparation of ethyl1-((3-((Ethoxycarbonyl)oxy)phenyl)sulfonyl)cyclopropane carboxylate

To a solution of 3-(cyclopropylsulfonyl)phenol (3.6 g, 18.16 mmol) inTHF (100 mL) was added n-butyllithium (18.75 mL, 46.87 mmol) drop wiseat −78° C. The reaction was stirred for 30 min at the same temperature.Ethyl chloroformate (5.27 mL, 55.39 mmol) was then added drop wise tothe reaction mixture at −78° C. The reaction mixture was allowed to warmup to room temperature and stirring was continued at room temperaturefor 2 h. After the reaction was completed, the mixture was quenched withsaturated aqueous NH₄Cl solution. The aqueous layer was extracted withEtOAc (3×). The organic extracts were combined and washed with brine,dried over Na₂SO₄, and filtered. The filtrate was concentrated to givethe title compound (6.4 g, 87.7% yield) without further purification.LCMS m/z=343.2 [M+H]⁺.

Step E: Preparation of 3-((1-(Hydroxymethyl)cyclopropyl)sulfonyl)phenol(Method BB6E)

To a solution of ethyl1-((3-((ethoxycarbonyl)oxy)phenyl)sulfonyl)cyclopropanecarboxylate (6.4g, 18.69 mmol) in THF (20 mL) was added 2.0 M solution of lithiumaluminum hydride (23.43 mL, 46.87 mmol) at 0° C. After stirring at 0° C.for 10 min, the reaction mixture was warmed up to room temperature thenstirred for another 3 h. The reaction mixture was carefully quenchedwith 1N NaOH at 0° C. to result in a thick suspension. To the suspensionwas added EtOAc (150 mL) and the reaction was stirred for 1 h at roomtemperature. The EtOAc layer was decanted from the suspension. 6N HCl(100 mL) was added and the mixture was stirred for 1 h to give a clearlayer. The layers were separated and the aqueous layer was extractedwith EtOAc (3×). The combined organic extracts were washed with waterand brine, dried over Na₂SO₄, and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound (3.74 g,76.9% yield) as a light yellow solid. LCMS m/z=229.4 [M+H]⁺; ¹H NMR (400M Hz, CDCl₃) δ ppm 1.04-1.07 (m, 2H), 1.58-1.61 (m, 2H), 3.67 (s, 2H),7.12-7.15 (m, 1H), 7.34 (dt, J=1.41, 7.70 Hz, 1H), 7.37 (d, J=7.76 Hz,1H), 7.38-7.40 (m, 1H), 9.18 (s, 1H).

Step F: Preparation of(S)-(1-((3-(Oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl) methanol

To a mixture of 3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenol (2.0 g,8.76 mmol) and potassium carbonate (3.63 g, 26.29 mmol) in acetone (30mL) was added (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (2.50 g,9.638 mmol). The reaction was heated at 75° C. overnight. The reactionmixture was cooled down to room temperature. The solid was separated byfiltration and washed with acetone (2×10 mL). The filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (2.55 g, 90.5% yield) as ayellowish liquid. LCMS m/z=285.0 [M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm1.05-1.08 (m, 2H), 1.62-1.66 (m, 2H), 2.64-2.74 (m, 1H), 2.78 (dd,J=2.69, 4.94 Hz, 1H), 2.94 (dd, J=4.19, 4.79 Hz, 1H), 3.35-3.39 (m, 1H),3.66 (bs, 2H), 3.98 (dd, J=6.08, 11.60 Hz, 1H), 4.37 (dd, J=2.76, 11.05Hz, 1H), 7.21-7.25 (m, 1H), 7.44-7.45 (m, 1H), 7.48-7.51 (m, 2H).

Example 1.12 Preparation of(S)-2,2-Difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl) ethanol(Method BB7) Step A: Preparation of Ethyl2,2-Difluoro-2-((3-methoxyphenyl)thio)acetate

To a suspension of sodium hydride (0.28 g, 6.99 mmol) in THF at 0° C.was added 3-methoxybenzenethiol (0.7 g, 4.99 mmol) in THF (2 mL) dropwise and stirred at room temperature for 30 min. The reaction was cooledback to 0° C. and added a solution of ethyl 2-bromo-2,2-difluoroacetate(0.70 mL, 5.49 mmol) in THF (0.5 mL) drop wise. The reaction was stirredat 0° C. for 2 h and quenched with ice. The aqueous layer was separatedand extracted with EtOAc (3×). The combined organic extracts were washedwith brine, dried over Na₂SO₄, and concentrated. The residue waspurified by silica gel column chromatography to give the title compound(1.26 g, 82% yield). LCMS m/z=263.2 [M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δppm 1.27 (t, J=7.15 Hz, 3H), 3.81 (s, 3H), 4.26 (q, J=7.15 Hz, 2H),6.98-7.01 (m, 1H), 7.14-7.15 (m, 1H), 7.18-7.20 (m, 1H), 7.29 (q, J=7.86Hz, 1H).

Step B: Preparation of Ethyl2,2-Difluoro-2-((3-methoxyphenyl)sulfonyl)acetate

To a solution of ethyl 2,2-difluoro-2-((3-methoxyphenyl)thio)acetate(1.26 g, 4.09 mmol) in DCM (75 mL) at 0° C. was added3-chlorobenzoperoxoic acid (3.36 g, 14.98 mmol) portion wise. Thereaction was stirred at room temperature overnight. The mixture wasfiltered through a pad of Celite® then washed with DCM. The filtrate wasadded NaHCO₃ then stirred for 30 min. The mixture was filtered through apad of Celite®. The filtrate was washed once with saturated NaHCO₃aqueous solution, brine, dried over Na₂SO₄, and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (1.01 g, 69% yield). LCMS m/z=295.2 [M+H]⁺.

Step C: Preparation of 2,2-Difluoro-2-((3-methoxyphenyl)sulfonyl)ethanol

To a solution of ethyl 2,2-difluoro-2-((3-methoxyphenyl)sulfonyl)acetate(261 mg, 0.887 mmol) at 0° C. was added of lithium aluminum hydride(2.0M, 0.375 mL, 0.750 mmol). After stirring at 0° C. for 10 min and atroom temperature for 3 h, the reaction mixture was quenched with 1N NaOHat 0° C. The suspension was added 10% of MeOH in DCM and stirred for 30minutes at room temperature. The mixture was filtered and washed with10% of MeOH in DCM (3×). Aqueous layer was extracted with 10% of MeOH inDCM (3×). The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel silica gel column chromatography to give the title compound(0.201 g, 89% yield). LCMS m/z=253.0 [M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δppm 3.89 (s, 3H), 4.29 (t, J=12.70 Hz, 2H), 7.29-7.32 (m, 1H), 7.46-7.47(m, 1H), 7.54 (t, J=7.88 Hz, 1H), 7.59 (m, 1H).

Step D: Preparation of 3-((1,1-Difluoro-2-hydroxyethyl)sulfonyl)phenol

To a solution of 2,2-difluoro-2-((3-methoxyphenyl)sulfonyl)ethanol(0.201 g, 0.668 mmol) in DCM (2 mL) at −78° C. under N₂ was added asolution of boron tribromide (0.142 mL, 1.501 mmol) slowly. The reactionwas stirred at −78° C. for 1 h then warmed up to room temperature andstirred for 1 h. After the reaction was completed, the mixture wascooled down to −20° C. then quenched with ^(i)PrOH. The mixture wasneutralized with NaHCO₃ aqueous solution to pH 7 then extracted with 20%of ^(i)PrOH in DCM. The combined organic extracts were washed once withbrine, separated, dried over Na₂SO₄, and filtered. The filtrate wasconcentrated to give the title compound without further purification.LCMS m/z=239.2 [M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 4.29 (t, J=12.72Hz, 2H), 7.24-7.27 (m, 1H), 7.45-7.46 (m, 1H), 7.49 (t, J=7.84 Hz, 1H),7.53-7.56 (m, 1H).

Step E: Preparation of(S)-2,2-Difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol

To a mixture of 3-((1,1-difluoro-2-hydroxyethyl)sulfonyl)phenol (0.132g, 0.555 mmol) and potassium carbonate (0.207 g, 1.501 mmol) in acetone(15 mL) was added (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (0.214g, 0.826 mmol). The reaction was heated at 75° C. overnight. The mixturewas cooled down to room temperature, filtered, and washed with acetone(2×5 mL). The filtrate was concentrated and the residue was purified bysilica gel column chromatography to give the title compound (0.205 g,69% yield). LCMS m/z=295.4 [M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 2.47(t, J=7.33 Hz, 1H), 2.79 (dd, J=2.18, 4.79 Hz, 1H), 2.95 (t, J=4.04 Hz,1H), 3.36-3.40 (m, 1H), 4.00 (dd, J=11.24, 5.94 Hz, 1H), 4.22-4.33 (m,2H), 4.38 (dd, J=11.12, 2.78 Hz, 1H), 7.31-7.39 (m, 1H), 7.47-7.52 (m,1H), 7.55 (t, J=7.96 Hz, 1H), 7.58-7.64 (m, 1H).

Example 1.13 Preparation of Quinoline-6-sulfonyl chloride Step A:Preparation of Methyl 3-(Quinolin-6-ylsulfonyl)propanoate

To a 5 mL microwave vial were added 6-bromoquinoline (200 mg, 0.96mmol), sodium 3-methoxy-3-oxopropane-1-sulfinate (0.84 g, 4.81 mmol),and copper (I) iodide (0.92 g, 4.81 mmol) followed by DMSO (2 mL). Thereaction was degassed (2×) with nitrogen then heated at 110° C.overnight. After the reaction was cooled down room temperature, it wasdiluted with EtOAc. The resulting mixture was filtered through a pad ofsilica gel, washed with EtOAc, and then concentrated. The residue waspurified by silica gel column chromatography to give the title compound(95 mg, 33% yield) as a yellow oil. LCMS m/z=280.2 [M+H]⁺; ¹H NMR (400MHz, CD₃OD) δ ppm 2.77 (t, J=7.20 Hz, 2H), 3.55 (s, 3H), 3.65 (t, J=7.20Hz, 2H), 7.72 (dd, J=8.46, 4.42 Hz, 1H), 8.17-8.22 (m, 1H), 8.24-8.29(m, 1H), 8.61 (dd, J=8.46, 1.14 Hz, 1H), 8.64 (d, J=2.02 Hz, 1H), 9.07(dd, J=4.29, 1.77 Hz, 1H).

Step B: Preparation of Quinoline-6-sulfonyl Chloride

To a solution of methyl 3-(quinolin-6-ylsulfonyl)propanoate (425 mg,1.52 mmol) in THF (15 mL) at room temperature was added sodium methoxide(0.35 μL 1.52 mmol). The reaction mixture was stirred for 30 min thenconcentrated to give methyl quinoline-6-sulfonate as a yellow solid.LCMS m/z=266.0 [M+H]⁺.

Methyl quinoline-6-sulfonate obtained above was dissolved in CH₂Cl₂(15.00 mL) at 0° C. Then NCS (0.20 g, 1.52 mmol) was added. The reactionwas stirred for 2 h. The reaction was quenched with brine then allowedto warm up to room temperature. The organic layer was separated andaqueous layer was washed with DCM. The combined organic layers werewashed with water and brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (199 mg, 57% yield) as a beigesolid. LCMS m/z=228.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 7.78 (dd,J=8.59, 4.29 Hz, 1H), 8.35 (d, J=1.52 Hz, 2H), 8.69 (dd, J=8.59, 1.52Hz, 1H), 8.86 (s, 1H), 9.14 (dd, J=4.29, 1.77 Hz, 1H).

Example 1.14 Preparation of tert-Butyl6-(Chlorosulfonyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate Step A:Preparation of 6-(Benzylthio)-1H-pyrrolo[3,2-b]pyridine

A mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridine (1.970 g, 10 mmol),phenylmethanethiol (1.291 mL, 11.00 mmol), DIEA (3.484 mL, 20.00 mmol),and Pd₂(dba)₃ (0.458 g, 0.500 mmol) in dioxane (10 mL) was added(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.579 g,1.000 mmol). The reaction was heated to 150° C. for 2 h under microwaveirradiation. After the reaction was cooled to room temperature, it wastaken up in EtOAc. The mixture was washed with NaHCO₃(3×) and brine,dried over MgSO₄ and concentrated. The residue was purified by silicagel column chromatography to give the title compound (2.31 g, 96.1%yield) as an orange solid. LCMS m/z=241.2 [M+H]⁺; ¹H NMR (400 M Hz,CD₃OD) δ 4.05 (s, 2H), 6.55 (d, J=4.04 Hz, 1H), 7.10-7.16 (m, 2H),7.16-7.25 (m, 3H), 7.56 (d, J=3.28 Hz, 1H), 7.73 (d, J=1.01 Hz, 1H),8.17 (d, J=1.77 Hz, 1H).

Step B: Preparation of tert-Butyl6-(Benzylthio)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

To a solution of 6-(benzylthio)-1H-pyrrolo[3,2-b]pyridine (2.304 g,9.587 mmol) and pyridine (1.551 mL, 19.17 mmol) in THF (20 mL) was added(BOC)₂O (2.511 g, 11.50 mmol). The reaction was stirred at roomtemperature for 18 h. The mixture was diluted with EtOAc, washed withwater (3×) and brine, dried over MgSO₄ and concentrated. The residue waspurified by silica gel column chromatography to give the title compound(2.59 g, 79.4% yield) as a yellow solid. LCMS m/z=341.4 [M+H]⁺; ¹H NMR(400 M Hz, CDCl₃) δ ppm 1.65 (s, 9H), 4.10 (s, 2H), 6.73 (d, J=3.28 Hz,1H), 7.14-7.33 (m, 5H), 7.79 (d, J=3.79 Hz, 1H), 8.34 (bs, 1H), 8.45 (d,J=2.02 Hz, 1H).

Step C: Preparation of tert-Butyl6-(Chlorosulfonyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (Method BB8C)

To a solution of tert-butyl6-(benzylthio)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2.583 g, 7.587mmol) in AcOH (10 mL)/H₂O (3.333 mL) was added NCS (3.039 g, 22.76mmol). The reaction was stirred for 5 hours. The mixture wasconcentrated. The residue was dissolved in DCM and washed with aqueousNaHCO₃. The aqueous layer was extracted with DCM (2×). The combinedorganics were dried over MgSO₄, filtered and concentrated. The residuewas purified by silica gel column chromatography to give the titlecompound (0.54 0 g, 22.5% yield) as a yellow solid. LCMS m/z=317.2[M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 1.72 (s, 9H), 6.94 (d, J=3.03 Hz,1H), 8.16 (d, J=3.54 Hz, 1H), 9.02 (bs, 1H), 9.16 (d, J=2.27 Hz, 1H).

Example 1.15 Preparation of1-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonyl Chloride(Method BB9) Step A: Preparation of7-(Benzylthio)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

From 7-bromo-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, thetitle compound was prepared using a similar method to the one describedin Example 1.14, Step A. LCMS m/z=272.8 [M+H]⁺.

Step B: Preparation of1-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonyl chloride

From 7-(benzylthio)-1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine,the title compound was prepared using a similar method to the onedescribed in Example 1.14, Step C. LCMS m/z=249.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.00 (s, 3H), 3.39-3.42 (m, 2H), 4.54-4.57 (m, 2H),7.24 (d, J=2.27 Hz, 1H), 8.22 (d, J=2.02 Hz, 1H).

Example 1.16 Preparation of3-Methyl-3H-imidazo[4,5-b]pyridine-6-sulfonyl chloride (Method BB10)Step A: Preparation of 5-(Benzylthio)-N²-methylpyridine-2,3-diamine

From 5-bromo-N²-methylpyridine-2,3-diamine, the title compound wasprepared using a similar method to the one described in Example 1.14,Step A. LCMS m/z=246.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.80 (d,J=4.55 Hz, 3H), 3.91 (s, 2H), 4.72 (s, 2H), 5.79 (q, J=4.55 Hz, 1H),6.72 (d, J=2.27 Hz, 1H), 7.17-7.22 (m, 3H), 7.24-7.29 (m, 2H), 7.31 (d,J=2.27 Hz, 1H)

Step B: Preparation of 6-(Benzylthio)-3-methyl-3H-imidazo[4,5-b]pyridine

To a solution of 5-(benzylthio)-N²-methylpyridine-2,3-diamine (0.195 g,0.795 mmol) in THF (5 mL) was added trimethoxymethane (4 mL, 36.56 mol)followed by addition of a few drops of TFA. The reaction was stirredovernight. The mixture was diluted with EtOAc, washed with water (3×)and brine, dried over MgSO₄ and concentrated. The residue was purifiedby silica gel column chromatography (1:1 EtOAc/hexane) to give the titlecompound (1.74 g, 87.5% yield) as a tan solid. LCMS m/z=256.4 [M+H]⁺; ¹HNMR (400 M Hz, CDCl₃) δ ppm 3.91 (s, 3H), 4.06 (s, 2H), 7.14-7.26 (m,5H), 8.03 (d, J=2.02 Hz, 1H), 8.08 (s, 1H), 8.35 (d, 1H).

Step C: Preparation of 3-Methyl-3H-imidazo[4,5-b]pyridine-6-sulfonylchloride

From 6-(benzylthio)-3-methyl-3H-imidazo[4,5-b]pyridine, the titlecompound was prepared using a similar method to the one described inExample 1.14, Step C. LCMS m/z=232.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δppm 4.02 (s, 3H), 8.29 (s, 1H), 8.71 (d, J=2.02 Hz, 1H), 9.10 (d, J=2.02Hz, 1H).

Example 1.17 Preparation of1-(2-Methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonylchloride (Method BB11) Step A: Preparation of7-Bromo-1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-][1,4]oxazine

To a solution of 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (0.430g, 2 mmol) in DMF was added sodium hydride (0.120 g, 3.000 mmol). Thereaction was stirred for 20 minutes. 1-Bromo-2-methoxyethane (0.207 mL,2.200 mmol) was added. The reaction was heated to 60° C. for 2 hours.The mixture was concentrated. The residue was taken up in EtOAc, washedwith water (3×) and brine, dried over MgSO₄ and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (0.451 g, 82.6% yield) as a white solid. LCMS m/z=273.0[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.36 (s, 3H), 3.39-3.47 (m, 4H),3.58 (t, J=5.43 Hz, 2H), 4.35 (t, J=4.80 Hz, 2H), 6.97 (d, J=2.02 Hz,1H), 7.55 (d, J=2.27 Hz, 1H).

Step B: Preparation of7-(Benzylthio)-1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-][1,4]oxazine

From7-bromo-1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, thetitle compound was prepared using a similar method to the one describedin Example 1.14, Step A. LCMS m/z=317.0 [M+H]⁺; ¹H NMR (400 M Hz, CDCl₃)δ ppm 3.29 (t, J=5.31 Hz, 2H), 3.32 (s, 3H), 3.37-3.45 (m, 4H), 3.96 (s,2H), 4.35 (t, J=4.55 Hz, 2H), 6.70 (d, J=2.02 Hz, 1H), 7.15-7.32 (m,5H), 7.53 (d, J=2.02 Hz, 1H).

Step C: Preparation of1-(2-Methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonylChloride

From7-(benzylthio)-1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine,the title compound was prepared using a similar method to the onedescribed in Example 1.14, Step C. LCMS m/z=292.8 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.36 (s, 3H), 3.52-3.56 (m, 4H), 3.63 (t, J=5.05 Hz,2H), 4.46-4.50 (m, 2H), 7.34 (d, J=2.27 Hz, 1H), 8.17 (d, J=2.02 Hz,1H).

Example 1.18 Preparation of 7-Fluoro-4-hydroxyquinoline-3-sulfonylChloride (Method BB12)

To sulfurochloridic acid (10.71 g, 91.9 mmol, 30 eq) at 0° C. was added7-fluoroquinolin-4-ol (500 mg, 3.06 mmol, 1.0 eq) under N₂ atmosphere.The resulting solution was stirred at 90° C. for 16 h. After cooling toroom temperature, the reaction mixture was added onto ice drop wise. Theresulting precipitate was filtered and the filter cake was washed withCH₃CN/H₂O (2:1), the filtrate was lyophilized to give the title compound(550 mg, 65% yield) as a white solid. LCMS m/z=261.9 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆): δ ppm 6.90 (br.s, 1H), 7.59 (td, J=8.9, 2.4 Hz, 1H), 7.78(dd, J=9.8, 2.5 Hz, 1H), 8.41 (dd, J=9.3, 6.0 Hz, 1H), 8.99 (s, 1H).

Example 1.19 Preparation of 4-Hydroxy-7-methylquinoline-3-sulfonylChloride (Method BB13)

To sulfurochloridic acid (10.98 g, 94.2 mmol) at 0° C. was added7-methylquinolin-4-ol (500 mg, 3.14 mmol) under N₂ atmosphere. Theresulting solution was stirred at 80° C. for 16 h. After cooling to roomtemperature, the reaction mixture was added onto ice drop wise. Theresulting precipitate was filtered and the filter cake was washed withCH₃CN/H₂O (3:1), the filtrate was lyophilized to give the title compound(250 mg, 17% yield) as a yellow solid, further purification could notimprove the purity. LCMS m/z=258.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δppm 2.57 (s, 3H), 7.64 (d, J=8.3 Hz, 1H), 7.82 (br.s., 1H), 8.26 (d,J=8.4 Hz, 1H), 9.07-9.15 (m, 1H).

Example 1.20 Preparation of 1H-Indole-3-sulfonyl Chloride (Method BB14)Step A: Preparation of 1H-Indole-sulfonic Acid

A solution of 1H-indole (2.0 g, 17.07 mmol) and sulfur trioxide pyridinecomplex (2.72 g, 17.07 mmol) in pyridine (10 mL) was refluxed understirring for 2 h and then was cooled to room temperature. The reactionmixture was diluted with water (20 mL) and washed with diethyl ether(2×20 mL). The aqueous phase was concentrated to give the title compoundwhich was used in the next step without further purification.

Step B: Preparation of 1H-Indole-3-sulfonyl Chloride

The 1H-indole-sulfonic acid pyridinium salt from the previous step wasdissolved in 40 mL of a 1:1 sulfolane (20 mL)-MeCN (20 mL) mixture. Thesolution was cooled to 0° C., and phosphoryl trichloride (6 mL, 64.57mmol) was added drop wise with stirring. The reaction mixture was heatedto 70° C. for 2 h, and then cooled to 0° C. Cold water (10 mL) was addeddrop wise to the reaction mixture. The precipitate was filtered, washedwith water and dried under reduced pressure to afford the title compound(1.7 g, 40% yield) as a brown color solid. LCMS m/z=216.0 [M+H]⁺; ¹H NMR(400 MHz, Acetone-d₆) δ ppm 7.38-7.46 (m, 2H), 7.69 (dd, J=6.57, 2.78Hz, 1H), 7.95 (dd, J=6.57, 2.78 Hz, 1H), 8.38 (s, 1H), 11.77 (bs, 1H).

Example 1.21 Preparation of 3-((3-Methoxyphenyl)sulfonyl)cyclobutanol

To a solution of 1-methoxy-3-(methylsulfonyl)benzene (200 mg, 1.074mmol) in THF (10 mL) at 0° C. was added dropwise n-butyllithium (2.5 Min hexane, 0.86 mL, 2.15 mmol), which resulted in formation of yellowishsuspension and stirring was continued for 1 h at 0° C. Then2-(chloromethyl)oxirane (99.37 mg, 1.07 mmol) was added drop wise at 0°C. The reaction was stirred at room temperature overnight and quenchedwith saturated aqueous NH₄Cl solution. The aqueous layer was extractedwith EtOAc (3×). The combined organic phase was washed with brine, driedover Na₂SO₄, and concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound (0.248 g, 86% yield) asa thick liquid. LCMS m/z=243.0 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm2.40-2.52 (m, 2H), 2.56-2.67 (m, 2H), 3.36 (quin, J=8.21 Hz, 1H), 3.87(s, 3H), 4.20 (quin, J=7.70 Hz, 1H), 7.17 (dt, J=7.14, 2.37 Hz, 1H),7.34-7.40 (m, 1H), 7.40-7.51 (m, 2H).

Example 1.22 Preparation of 2-((3-Fluoro-5-methoxyphenyl)thio)ethanol

A mixture of 1-bromo-3-fluoro-5-methoxybenzene (0.5 g, 2.44 mmol),2-mercaptoethanol (0.210 g, 2.683 mmol), DIEA (0.94 mL, 5.37 mmol),Pd2(dba)3 (0.22 g, 0.24 mmol), and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.14 g, 0.24mmol) in DMF (2 mL) was heated to 110° C. overnight. After cooling downto room temperature, the mixture was diluted with EtOAc and water. Themixture was filtered through a pad of celite. The aqueous layer wasextracted with EtOAc (3×). The combined organic layer was washed withbrine, dried over Na₂SO₄, and filtered. The filtrate was concentrated togive the title compound without further purification.

Example 1.23 Preparation of7-(Benzylthio)-1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazineStep A: Preparation of Ethyl2-((5-Bromo-4-methyl-3-nitropyridin-2-yl)oxy)acetate

To a solution of 5-bromo-2-chloro-4-methyl-3-nitro-pyridine (5.00 g,19.9 mmol) in ethyl 2-hydroxyacetate (12.42 g, 119 mmol) at roomtemperature was added DBU (9.08 g, 59.7 mmol) dropwise. The color of thereaction mixture changed from yellow to puce. The mixture was stirred at100° C. for 8 hours and then cooled to room temperature. The reactionwas then quenched with 30 mL of water and extracted with ethyl acetate(2×20 mL). The combined organic phase was washed with brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography to give thetitle compound (2.0 g, 29% yield, 91% purity) as a yellow solid.

Step B: Preparation of7-Bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

To a solution of ethyl2-((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)acetate (2.00 g, 5.70 mmol,91% purity 1.0 eq) in EtOH (4 mL) and AcOH (10 mL) at room temperaturewas added zinc powder (2.05 g, 31.4 mmol). The reaction was stirred at100° C. for 1 hour. After cooling to room temperature, the solution wasconcentrated in vacuo. To the residue was added MeOH (20 mL) and pH wasadjusted to 9 by ammonia. The mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (1.40 g, crude) as abrown solid, which was used in the next step without furtherpurification.

Step C: Preparation of7-Bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

To the solution of7-bromo-8-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (1.40 g crude,5.76 mmol, 1.0 eq) in THF (5 mL) was added BH₃THF (23 mL, 1 M solutionin THF, 23 mmol, 4.0 eq) at 0° C. under N₂ atmosphere. The mixture wasthen heated to 80° C. for 6 hours. After cooling to room temperature,the reaction was quenched by adding 3 mL of H₂O and 3 mL of MeOH. Themixture was concentrated in vacuo and purified by silica gel columnchromatography to give the title compound (800 mg, 54% yield, 89%purity) as a white solid.

Step D: Preparation of7-Bromo-1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

To a solution of7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (800 mg, 3.11mmol, 89% purity) in DMF (6 mL) under N₂ atmosphere was added NaH(167.60 mg, 60% purity, 4.19 mmol) and then stirred at 0° C. for 1 hour.To the above solution was added iodomethane (13.00 g, 91.4 mmol) at 0°C. and then stirred at 20° C. for additional 1 h. The reaction mixturewas quenched by addition of saturated aqueous solution of NH₄Cl (4 mL),diluted with H₂O (4 mL) and extracted with ethyl acetate (3×8 mL). Thecombined organic layer was washed with brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography to give the title compound(690 mg, 65% yield, 80% purity) as a white oil.

Step E: Preparation of7-(Benzylthio)-1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

To a microwave tube were added phenylmethanethiol (1.46 g, 11.7 mmol,3.0 eq), 7-bromo-1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine(950 mg, 3.91 mmol), dioxane (6.00 mL), Pd(dppf)Cl₂.CH₂Cl₂ (1.43 g, 1.96mmol, 0.50 eq), tri-tert-butylphosphine (791 mg, 3.91 mmol, 1.0 eq) andDIEA (2.02 g, 15.6 mmol, 4.0 eq) under N₂ atmosphere. The sealed tubewas heated at 150° C. for 6 hours under microwave irradiation. Aftercooling, the mixture was diluted with H₂O (20 mL) and extracted withethyl acetate (3×20 mL). The combined organic phase was washed withbrine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by prep-HPLC (basic condition) to givethe title compound (500 mg, 44% yield) as a brown oil. LCMS m/z 287.4[M+H]⁺; ¹H NMR (CDCl₃, 400 MHz): δ ppm 2.17 (s, 3H), 2.62 (s, 3H),3.03-3.11 (m, 2H), 3.89 (s, 2H), 4.31-4.38 (m, 2H), 7.06-7.15 (m, 2H),7.18-7.26 (m, 3H), 7.94 (s, 1H).

Example 1.24 Preparation of(R)-7-(Benzylthio)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazineStep A: Preparation of (R)-Methyl2-((5-bromo-3-nitropyridin-2-yl)oxy)propanoate

To a solution of 5-bromo-2-chloro-3-nitropyridine (8.00 g, 33.7 mmol,1.0 eq), methyl (2R)-2-hydroxypropanoate (10.52 g, 101 mmol, 3.0 eq) inMeCN (250 mL) was added K₂CO₃ (18.63 g, 135 mmol, 4.0 eq). The reactionwas stirred at 75° C. for 15 h. After cooling, the mixture was filteredand the filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatography to give the title compound (4.84 g, 47% yield)as yellow oil.

Step B: Preparation of(R)-7-Bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

To a solution of (R)-methyl2-((5-bromo-3-nitropyridin-2-yl)oxy)propanoate (4.80 g, 15.7 mmol) inAcOH (250 mL) was added Fe powder (4.39 g, 78.7 mmol), and then themixture was heated to 80° C. for 1 h. After cooling to room temperature,the mixture was filtered and the filtrate was concentrated in vacuo togive the title compound (10 g) without further purification.

Step C: Preparation of(R)-7-Bromo-1,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

To a solution of(R)-7-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (4.81 gcrude, 19.8 mmol) in acetone (80 mL) was added MeI (3.98 g, 28.0 mmol)and K₂CO₃ (2.74 g, 19.8 mmol). The mixture was stirred at 50-70° C. for15 h. After cooling, the reaction mixture was filtered, and the filtratewas concentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (1.24 g, 24% yield, 88%purity) as a white solid. LCMS m/z=256.9 [M+H]⁺.

Step D: Preparation of(R)-7-Bromo-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

To a solution of(R)-7-bromo-1,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (400 mg,1.37 mmol, 88% purity) in THF (40 mL) was added BH₃THF (15.6 mL, 1 Msolution in THF, 15.6 mmol) dropwise at 0° C. under N₂ atmosphere. Themixture was then stirred at 25° C. for 15 h. The reaction mixture wasquenched by adding MeOH (4 mL) at 0° C., and then 1 M HCl was added toadjust pH<7. The mixture was then heated to reflux for 1 hour. Aftercooling, 1 M NaOH aqueous solution was added to adjust pH>7. Thereaction mixture was diluted with H₂O (20 mL) and extracted with ethylacetate (3×20 mL). The combined organic phase was washed with brine (30mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel chromatography to give the titlecompound (269 mg, 71% yield) as a yellow solid. LCMS (ESI): m/z=242.9[M+H]⁺.

Step E: Preparation of(R)-7-(Benzylthio)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

From (R)-7-bromo-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine,the title compound was prepared using a similar method to the onedescribed in Example 1.23, Step E. LCMS m/z=287.1 [M+H]⁺; ¹H NMR (CDCl₃,400 MHz): δ ppm 1.42 (d, J=6.4 Hz, 3H), 2.73 (s, 3H), 2.98 (dd, J=11.5,8.4 Hz, 1H), 3.16 (dd, J=11.6, 2.6 Hz, 1H), 3.97 (s, 2H), 4.48 (dqd,J=8.5, 6.3, 2.6 Hz, 1H), 6.66 (d, J=2.0 Hz, 1H), 7.18-7.32 (m, 5H), 7.57(d, J=2.0 Hz, 1H).

Example 1.25 Preparation of(3S)-7-Benzylsulfanyl-1,3-dimethyl-2,3-dihydropyrido[2,3-b][1,4]oxazineStep A: Preparation of Methyl(2S)-2-[(5-Bromo-3-nitro-2-pyridyl)oxy]propanoate

To a solution of 5-bromo-2-chloro-3-nitro-pyridine (8.00 g, 33.7 mmol),methyl (2S)-2-hydroxypropanoate (10.52 g, 101 mmol) in MeCN (100 mL) wasadded K₂CO₃ (18.63 g, 135 mmol). The mixture was stirred at 75° C. for15 hours. After cooling, the reaction mixture was filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (6.10 g, 59% yield) as ayellow oil.

Step B: Preparation of(3S)-7-Bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one

To a solution of (S)-methyl2-((5-bromo-3-nitropyridin-2-yl)oxy)propanoate (5.00 g, 16.4 mmol) inAcOH (50 mL) was added Fe powder (4.58 g, 82.0 mmol), and then themixture was heated to 80° C. for 1 h. The reaction mixture was filteredand concentrated in vacuo. The residue was purified by basic resin togive the title compound (3.58 g, 90% yield) without furtherpurification.

Step C: Preparation of(3S)-7-Bromo-3-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

To a solution of (3S)-7-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one(2.20 g, 9.05 mmol) in THF (100 mL) was added BH₃THF (90.5 mL, 1 Msolution in THF, 90.5 mmol) at 0° C. The reaction was then stirred at25° C. for 15 h. The reaction mixture was quenched by adding MeOH (4.0mL) at 0° C., and then HCl (1 M, 2.0 mL) was added to adjust pH<7. Themixture was refluxed for 1 h and then cooled to room temperature. NaOH(1 M aqueous solution, 4.0 mL) was added to make pH>7. The aqueous phasewas extracted with DCM (3×100 mL). The combined organic phase was washedwith brine (2×30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (679 mg, 33% yield) as a whitesolid.

Step D: Preparation of(3S)-7-Bromo-1,3-dimethyl-2,3-dihydropyrido[2,3-b][1,4]oxazine

To a solution of (3S)-7-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one(100 mg, 411 μmol) in DMF (20 mL) was added NaH (104 mg, 2.59 mmol, 60%purity) at 0° C. under N₂ atmosphere. The mixture was stirred at 25° C.for 15 h before quenching with ice water. The mixture was then extractedwith ethyl acetate (3×20 mL). The combined organic phase was washed withbrine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel chromatography to give thetitle compound (80 mg, 80% yield) as a white solid.

Step E: Preparation of(3S)-7-Benzylsulfanyl-1,3-dimethyl-2,3-dihydropyrido[2,3-b][1,4]oxazine

From (3S)-7-bromo-1,3-dimethyl-2,3-dihydropyrido[2,3-b][1,4]oxazine, thetitle compound was prepared using a similar method to the one describedin Example 1.23, Step E. LCMS m/z=287.1 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz):δ ppm 1.41 (d, J=6.4 Hz, 3H), 2.72 (s, 3H), 2.97 (dd, J=11.5, 8.4 Hz,1H), 3.15 (dd, J=11.5, 2.5 Hz, 1H), 3.96 (s, 2H), 4.43-4.53 (m, 1H),6.64 (d, J=1.9 Hz, 1H), 7.16-7.30 (m, 5H), 7.55 (d, J=2.0 Hz, 1H).

Example 1.26 Preparation of7-Benzylsulfanyl-1,3,3-trimethyl-2H-pyrido[2,3-b][1,4]oxazine Step A:Preparation of2-Bromo-N-(5-bromo-2-hydroxypyridin-3-yl)-2-methylpropanamide

To a solution of 3-amino-5-bromopyridin-2-ol (4.00 g, 21.2 mmol, 1.0 eq)in THF (40 mL) was added TEA (6.42 g, 63.5 mmol) and2-bromo-2-methyl-propanoyl bromide (5.35 g, 23.3 mmol) at 0° C. Thereaction was stirred at 17° C. for 2 h. The mixture was diluted with H₂O(60 mL) and extracted with ethyl acetate (2×30 mL). The combined organicphase was washed with brine (30 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound (6.30 g,crude) as a white solid without further purification. LCMS: m/z=336.9.[M+H]⁺.

Step B: Preparation of7-Bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

To a solution of2-bromo-N-(5-bromo-2-hydroxypyridin-3-yl)-2-methylpropanamide (5.30 g,15.7 mmol) in DMF (130 mL) was added K₂CO₃ (6.50 g, 47.0 mmol). Themixture was stirred at 70° C. for 8 h under N₂ atmosphere. Aftercooling, the reaction mixture was concentrated in vacuo. The residue waspurified by silica gel column chromatography to give the title compound(2.70 g, 67% yield) as a yellow solid.

Step C: Preparation of7-Bromo-3,3-dimethyl-1,2-dihydropyrido[2,3-b][1,4]oxazine

To a solution of7-bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (2.70 g, 10.5mmol) in THF (20 mL) was added BH₃THF (31.5 mL, 1 M solution in THF,31.5 mmol) at 0° C. under N₂ atmosphere. The reaction was stirred at 80°C. for 4 h. After cooling, the reaction mixture was quenched by additionof H₂O (3 mL) and MeOH (3 mL). The mixture was concentrated in vacuo togive the title compound (2.80 g, crude) as a yellow solid. LCMSm/z=243.0 [M+H]⁺.

Step D: Preparation of7-Bromo-1,3,3-trimethyl-2H-pyrido[2,3-b][1,4]oxazine

To a solution of7-bromo-3,3-dimethyl-1,2-dihydropyrido[2,3-b][1,4]oxazine (2.80 g, 11.5mmol) in DMF (30 mL) was added NaH (691 mg, 17.3 mmol, 60% purity) at 0°C. for 30 minutes under N₂ atmosphere. Then iodomethane (2.45 g, 17.3mmol) was added at 0° C. The reaction was stirred at 15° C. for 1 h. Themixture was quenched by addition of saturated aqueous solution of NH₄Cl(20 mL), and then extracted with ethyl acetate (2×20 mL). The combinedorganic phase was washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography to give the title compound (150 mg) asa white solid.

Step E: Preparation of7-Benzylsulfanyl-1,3,3-trimethyl-2H-pyrido[2,3-b][1,4]oxazine

From 7-bromo-1,3,3-trimethyl-2H-pyrido[2,3-b][1,4]oxazine, the titlecompound was prepared using a similar method to the one described inExample 1.23, Step E. LCMS m/z=301.1 [M+H]⁺; ¹H NMR (CDCl₃, 400 MHz): δppm 1.38 (s, 6H), 2.75 (s, 3H), 2.91-2.98 (m, 2H), 3.96 (s, 2H), 6.65(d, J=2.0 Hz, 1H), 7.16-7.32 (m, 5H), 7.59 (d, J=2.0 Hz, 1H).

Example 1.27 Preparation of7-Benzylsulfanyl-1-methyl-spiro[2H-pyrido[2,3-b][1,4]oxazine-3,1′-cyclopropane]Step A: Preparation of Methyl1-[(5-Bromo-3-nitro-2-pyridyl)oxy]cyclopropanecarboxylate

To a mixture of methyl 1-hydroxycyclopropanecarboxylate (3.00 g, 25.82mmol) in THF (100 mL) was added NaH (1.55 g, 38.7 mmol, 60% purity) inportions at 0° C. under N₂ atmosphere. The mixture was stirred at 0° C.for 30 minutes, then 5-bromo-2-chloro-3-nitro-pyridine (6.13 g, 25.8mmol) in THF (20 mL) was added dropwise. The mixture was stirred at 0°C. for 1.5 h. The solution was quenched with water (50 mL) and thenextracted with ethyl acetate (3×100 mL). The combined organic layers waswashed with brine (2×200 mL), dried over Na₂SO₄, filtered, and thenconcentrated in vacuo. The residue was purified by chromatography togive the title compound (5.35 g, 65% yield) as a red solid. LCMSm/z=316.9 [M+H]⁺.

Step B: Preparation of7-Bromospiro[1H-pyrido[2,3-b][1,4]oxazine-3,1′-cyclopropane]-2-one

To a mixture of methyl1-[(5-bromo-3-nitro-2-pyridyl)oxy]cyclopropanecarboxylate (2.00 g, 6.31mmol) in AcOH (8 mL) and EtOH (3 mL) was added zinc powder (2.10 g, 32.1mmol). The reaction was then stirred at 100° C. for 1 h. After cooling,the mixture was filtered, and the filtrate was concentrated in vacuo togive the title compound (2.20 g) as a yellow solid without furtherpurification. LCMS m/z=255.0 [M+H]⁺.

Step C: Preparation of7-Bromospiro[1,2-dihydropyrido[2,3-b][1,4]oxazine-3,1′-cyclopropane]

To a solution of7-bromospiro[1H-pyrido[2,3-b][1,4]oxazine-3,1′-cyclopropane]-2-one (3.00g, 10.2 mmol) in THF (20 mL) was added borane; tetrahydrofuran (40.9 mL,1 M solution in THF, 40.9 mmol) at 0° C. under N₂ atmosphere. Thereaction was then stirred at 80° C. for 3 h. After cooling to 20° C.,methanol (10 mL) was added, and the resulting solution was concentratedin vacuo. The residue was diluted in ethyl acetate (15 mL) and washedwith saturated aqueous NaHCO₃ (2×20 mL), water (2×20 mL), brine (2×20mL). The organic layer was then concentrated in vacuo to give the titlecompound (1.50 g, 28% yield) as a yellow oil. LCMS m/z=240.9 [M+H]⁺.

Step D: Preparation of7-Bromo-1-methyl-spiro[2H-pyrido[2,3-b][1,4]oxazine-3,1′-cyclopropane]

To a solution of7-bromospiro[1,2-dihydropyrido[2,3-b][1,4]oxazine-3,1′-cyclopropane](1.00 g, 1.91 mmol, 46% purity, 1.0 eq) in DMF (25 mL) was added NaH (60mg, 2.48 mmol, 60% purity, 0.78 eq) at 0° C., after stirring for 5minutes, iodomethane (542 mg, 3.82 mmol, 2.0 eq) was added. The reactionwas stirred at 0° C. for 1.5 hours and then quenched with water (30 mL)and brine (30 mL). The reaction solution was extracted with ethylacetate (2×50 mL). The combined organic layers was washed with water(2×50 mL) and brine (2×50 mL), and then concentrated in vacuo. Theresidue was purified by chromatography to give the title compound (400mg, 66% yield) as a yellow oil. LCMS m/z=255.0 [M+H]⁺; ¹H NMR (300 MHz,CDCl₃): δ ppm 0.71-0.79 (m, 2H), 1.13-1.22 (m, 2H), 2.91 (s, 3H), 3.22(s, 2H), 6.97 (d, J=2.1 Hz, 1H), 7.56 (d, J=2.1 Hz, 1H).

Step E: Preparation of7-Benzylsulfanyl-1-methyl-spiro[2H-pyrido[2,3-b][1,4]oxazine-3,1′-cyclopropane]

From7-bromo-1-methyl-spiro[2H-pyrido[2,3-b][1,4]oxazine-3,1′-cyclopropane],the title compound was prepared using a similar method to the onedescribed in Example 1.23, Step E (except acidic HPLC condition). LCMSm/z=299.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ ppm 0.72-0.82 (m, 2H),0.91-1.00 (m, 2H), 2.79 (s, 3H), 3.20 (s, 2H), 4.13 (s, 2H), 6.93 (d,J=1.8 Hz, 1H), 7.19-7.30 (m, 5H), 7.31 (d, J=2.0 Hz, 1H).

Example 1.28 Preparation of(S)-(1-((3-(Oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclobutyl) methanol StepA: Preparation of Ethyl 1-((3-Methoxyphenyl)thio)cyclobutanecarboxylate

To a solution of 3-methoxybenzenethiol (0.88 mL, 7.13 mmol) in EtOH (20mL) was added powdered potassium hydroxide (0.44 g, 7.85 mmol), followedby ethyl 1-bromocyclobutanecarboxylate (1.63 g, 7.85 mmol). The reactionwas heated to reflux for 3 h and then cooled to room temperature. Thesolid was separated by filtration and rinsed with EtOH (20 mL). Thefiltrate was concentrated under reduced pressure. The residue wasdissolved in DCM (50 mL) and washed with saturated NaHCO₃ aqueoussolution (50 mL). The aqueous layer was back extracted with DCM (50 mL).The combined organic extracts were washed with brine, dried over Na₂SO₄,and filtered. The filtrate was concentrated to give the title compound(1.7 g, 90% yield) without further purification. LCMS m/z=267.4 [M+H]⁺;¹H NMR (400 MHz, CDCl₃) δ ppm 1.21 (t, J=7.07 Hz, 3H), 1.86-1.97 (m,1H), 2.14-2.32 (m, 3H), 2.66-2.75 (m, 2H), 3.79 (s, 3H), 4.16 (q, J=7.07Hz, 2H), 6.82 (dd, J=8.34, 2.53 Hz, 1H), 6.91-6.98 (m, 2H), 7.20 (t,J=8.08 Hz, 1H).

Step B: Preparation of Ethyl1-((3-Methoxyphenyl)sulfonyl)cyclobutanecarboxylate

To a solution of ethyl 1-((3-methoxyphenyl)thio)cyclobutanecarboxylate(0.60 g, 2.25 mmol) in dioxane/H₂O (20 mL/5 mL, 4:1) was added inseveral portions of Oxone® (4.15 g, 6.76 mmol). The white suspension wasstirred at room temperature for 3 h. The white solid was separated byfiltration and washed with dioxane (20 mL). The filtrate wasconcentrated and the resulting aqueous solution was extracted with DCM(3×40 mL). The combined organic extracts were washed with saturatedNaHCO₃ aqueous solution, brine and dried over Na₂SO₄ then filtered. Thefiltrate was concentrated to give the title compound (0.6 g, 88% yield)as a solid without further purification. LCMS m/z=299.4 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 1.17 (t, J=7.07 Hz, 3H), 1.88-2.05 (m, 1H),2.05-2.19 (m, 1H), 2.55-2.66 (m, 2H), 2.98 (ddd, J=13.89, 9.98, 7.71 Hz,2H), 3.86 (s, 3H), 4.12 (q, J=7.07 Hz, 2H), 7.18 (ddd, J=6.95, 2.53,2.40 Hz, 1H), 7.33 (t, J=1.01 Hz, 1H), 7.39-7.47 (m, 2H).

Step C: Preparation of (1-((3-Methoxyphenyl)sulfonyl)cyclobutyl)methanol

To a solution of ethyl1-((3-methoxyphenyl)sulfonyl)cyclobutanecarboxylate (0.6 g, 1.99 mmol)in THF at 0° C. was added lithium aluminum hydride (2.0 M, 1.13 mL, 2.25mmol). After stirring at 0° C. for 10 min and at room temperature for 2h, the reaction was quenched with 1N NaOH at 0° C. To the suspension wasadded MeOH/DCM (10%) and stirred for 30 min at room temperature. Thesuspension was filtered and washed with MeOH/DCM (10%, 3×). The aqueouslayer was extracted with MeOH/DCM (3×). The combined organic extractswere washed with brine, dried over Na₂SO₄, and filtered. The filtratewas concentrated to give the title compound (0.55 g, 92% yield) withoutfurther purification. LCMS m/z=257.2 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δppm 1.94-2.10 (m, 4H), 2.65-2.80 (m, 2H), 3.49 (s, 1H), 3.83 (s, 2H),3.88 (s, 3H), 7.21 (dt, J=7.52, 1.17 Hz, 1H), 7.38 (t, J=2.27 Hz, 1H),7.42-7.55 (m, 2H).

Step D: Preparation of 3-((1-(hydroxymethyl)cyclobutyl)sulfonyl)phenol

To a solution of (1-((3-methoxyphenyl)sulfonyl)cyclobutyl)methanol (0.55g, 2.08 mmol) in CH₂Cl₂ (2 mL) at −78° C. was added a solution of borontribromide (0.43 mL, 4.51 mmol) slowly under N₂. The reaction mixturewas stirred at −78° C. for 5 h then stirred at room temperature for 2 h.The reaction was cooled down to −20° C. and quenched with ^(i)PrOH. Themixture was neutralized with aqueous NaHCO₃ solution to pH 7. Theresulting mixture was extracted with ^(i)PrOH/DCM (20%). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, and filteredthen concentrated to give the title compound (0.49 g, 84% yield) withoutfurther purification. LCMS m/z=243.0 [M+H]⁺.

Step E: Preparation of(S)-(1-((3-(Oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclobutyl) methanol

To a mixture of 3-((1-(hydroxymethyl)cyclobutyl)sulfonyl)phenol (280 mg,1.16 mmol) and potassium carbonate (0.48 g, 3.47 mmol) in acetone (10mL) was added (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (0.30 g,1.16 mmol). The reaction mixture was heated at 70° C. overnight. Aftercooling down to room temperature, the solid material was filteredthrough a pad of Celite® and washed with acetone (2×5 mL). The filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound (0.30 g, 84% yield). LCMSm/z=299.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.91-2.09 (m, 4H),2.67-2.76 (m, 2H), 2.78 (dd, J=4.80, 2.53 Hz, 1H), 2.87 (t, J=6.32 Hz,1H), 2.93 (d, J=4.04 Hz, 1H), 3.30-3.40 (m, 1H), 3.83 (d, J=6.32 Hz,2H), 3.98 (dd, J=11.12, 6.06 Hz, 1H), 4.37 (dd, J=11.24, 2.65 Hz, 1H),7.22-7.26 (m, 1H), 7.41 (t, J=1.26 Hz, 1H), 7.45-7.53 (m, 2H).

Example 1.29 Preparation of(S)-2-Methyl-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)propan-1-ol StepA: Preparation of Ethyl 2-((3-Hydroxyphenyl)thio)-2-methylpropanoate

A solution of 3-mercaptophenol (1.0 g, 7.93 mmol) in MeOH (20 mL) wasadded aqueous 1.0 N sodium hydroxide (8.72 mL, 8.72 mmol) dropwise overa period of 30 min at −5° C. The reaction was stirred at −5° C. for 1 h.A solution of ethyl 2-bromo-2-methylpropanoate (1.70 g, 8.72 mmol) inMeOH (5 mL) was added at −5° C. over a period of 15 min. The reactionwas stirred at room temperature for 24 h. The mixture was concentrated.The residue was treated with 25 mL of water and 100 mL of TBME. Afterextraction and phase separation, the organic phase was washed with 50 mLof saturated NaHCO₃ and 50 mL of brine. The combined organic phase wasdried over Na₂SO₄ and filtered. The filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (1.47 g, 77% yield). LCMS m/z=241.2 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 1.23 (t, J=7.07 Hz, 3H), 1.51 (s, 6H), 4.13 (q, J=7.24Hz, 2H), 6.85 (ddd, J=8.08, 2.53, 1.01 Hz, 1H), 6.98 (t, J=2.53 Hz, 1H),7.03 (dt, J=7.64, 1.36 Hz, 1H), 7.18 (t, J=7.83 Hz, 1H).

Step B: Preparation of Ethyl2-((3-Hydroxyphenyl)sulfonyl)-2-methylpropanoate

To a solution of ethyl 2-((3-hydroxyphenyl)thio)-2-methylpropanoate (500mg, 2.08 mmol) in dioxane/water (4:1, 30 mL) were added in severalportions of Oxone® (3.84 g, 6.24 mmol). The white suspension was stirredat room temperature for 3-4 h. The white solid was filtered and washedwith dioxane (20 mL) and the filtrate was concentrated. The resultingaqueous solution was extracted with DCM (3×40 mL). The combined organicextracts were washed with saturated NaHCO₃ aqueous solution, brine,dried over Na₂SO₄ and filtered. The filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (0.54 g, 91% yield). LCMS m/z=273.4 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 1.17 (t, J=7.07 Hz, 3H), 1.64 (s, 6H), 4.13 (q, J=7.16Hz, 2H), 6.77 (s, 1H), 7.16-7.20 (m, 1H), 7.36-7.47 (m, 3H).

Step C: Preparation of 3-((1-Hydroxy-2-methylpropan-2-yl)sulfonyl)phenol

To a solution of ethyl 2-((3-hydroxyphenyl)sulfonyl)-2-methylpropanoate(500 mg, 1.84 mmol) in THF (30 mL) at 0° C. was added lithium aluminumhydride (2.0 M in THF, 1.10 mL, 2.20 mmol). After stirring at 0° C. for10 min and at room temperature for 3 h, the reaction was quenched withwater and aqueous HCl (6.0 M) at 0° C. then warmed up to roomtemperature. To the resulting mixture was added ^(i)PrOH/DCM (20%) thenit was stirred for 30 min at room temperature. The aqueous layer wasextracted with ^(i)PrOH/DCM (20%, 3×). The combined organic layer waswashed with brine, dried over Na₂SO₄, and filtered. The filtrate wasconcentrated to give the title compound (411 mg, 97% yield) withoutfurther purification. LCMS m/z=231.0 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δppm 1.29 (s, 6H), 3.65 (s, 2H), 7.12 (ddd, J=8.15, 2.46, 1.01 Hz, 1H),7.26 (t, J=2.27 Hz, 1H), 7.29-7.34 (m, 1H), 7.43 (t, J=7.96 Hz, 1H).

Step D: Preparation of(S)-2-Methyl-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)propan-1-ol

To a mixture of 3-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)phenol (411mg, 1.79 mmol) and potassium carbonate (0.76 g, 5.51 mmol) in acetone(30 mL) was added (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (0.52 g,2.02 mmol). The reaction mixture was heated at 70° C. overnight. Thereaction mixture was cooled down to room temperature. The solid wasfiltered and washed with acetone (2×10 mL). The filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (0.50 g, 95% yield) as a thickliquid. LCMS m/z=287.0 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.31 (s,6H), 2.78 (dd, J=4.80, 2.78 Hz, 1H), 2.87-2.97 (m, 2H), 3.34-3.40 (m,1H), 3.74 (d, J=4.29 Hz, 2H), 3.98 (dd, J=11.24, 5.94 Hz, 1H), 4.36 (dd,J=11.12, 2.78 Hz, 1H), 7.22-7.26 (m, 1H), 7.41 (t, J=1.01 Hz, 1H),7.45-7.51 (m, 2H).

Example 1.30 Preparation of(R)-8-((1-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amineStep A: Preparation of (R)-tert-Butyl1-Oxa-8-azaspiro[4.5]decan-3-ylcarbamate

The title compound was prepared using a similar method to the onedescribed in Method B, Step A.

Step B: Preparation of (R)-tert-Butyl(8-((1-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

From 1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonylchloride and (R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,the title compound was prepared using a similar method to the onedescribed in Method B, Step B. LCMS m/z=469.4 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.42 (s, 9H), 1.59-1.83 (m, 5H), 2.05 (dd, J=13.14, 8.08Hz, 1H), 2.73-2.84 (m, 2H), 2.98 (s, 3H), 3.33-3.42 (m, 5H), 3.51 (dd,J=9.09, 5.56 Hz, 1H), 3.85-3.93 (m, 1H), 4.05-4.15 (m, 1H), 4.51 (t,J=4.55 Hz, 1H), 7.13 (d, J=2.02 Hz, 1H), 7.75 (d, J=2.02 Hz, 1H).

Step C: Preparation of(R)-8-((1-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine

To a solution of (R)-tert-butyl(8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(189.0 mg, 0.40 mmol) in CH₂Cl₂ (10 mL) was added HCl (1.01 mL, 4.03mmol) in dioxane. The reaction mixture was stirred at room temperatureovernight. Next day, a white precipitation was observed. The reactionwas quenched with water then neutralized with saturated NaHCO₃ aqueoussolution. The resulting solution was extracted with ^(i)PrOH/DCM (20%,2×). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give the title compound (149 mg, 92% yield) as a palesolid. LCMS m/z=369.4 [M+H]+; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.50 (dd,J=13.01, 6.19 Hz, 1H), 1.60-1.78 (m, 2H), 1.78-1.86 (m, 2H), 2.07 (dd,J=12.88, 7.58 Hz, 1H), 2.74-2.87 (m, 2H), 2.97 (s, 3H), 3.33-3.46 (m,6H), 3.50-3.57 (m, 1H), 3.86 (dd, J=8.84, 5.81 Hz, 1H), 4.51 (t, J=4.55Hz, 2H), 7.13 (d, J=2.02 Hz, 1H), 7.75 (d, J=2.27 Hz, 1H).

Example 1.31 Preparation of(R)-8-(Quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine Step A:Preparation of (R)-tert-Butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate

The title compound was prepared using a similar method to the onedescribed in Method B, Step A.

Step B: Preparation of (R)-tert-Butyl(8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

From quinoline-6-sulfonyl chloride and (R)-tert-butyl1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate, the title compound wasprepared using a similar method to the one described in Method B, StepB. LCMS m/z=448.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.40 (s, 9H),1.59 (dd, J=13.14, 6.06 Hz, 1H), 1.66-1.74 (m, 2H), 1.75-1.83 (m, 2H),1.97-2.05 (m, 1H), 2.77-2.89 (m, 2H), 3.41-3.51 (m, 3H), 3.84 (dd,J=9.22, 6.19 Hz, 1H), 4.01-4.12 (m, 1H), 7.69 (dd, J=8.34, 4.29 Hz, 1H),8.07 (dd, J=8.84, 2.02 Hz, 1H), 8.23 (d, J=8.84 Hz, 1H), 8.48 (d, J=2.02Hz, 1H), 8.58 (d, J=7.58 Hz, 1H), 9.03 (dd, J=4.29, 1.77 Hz, 1H).

Step C: Preparation of(R)-8-(Quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine

To a solution of (R)-tert-butyl(8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(398 mg, 0.89 mmol) in DCM (12 mL) at room temperature was added TFA(0.68 mL, 8.89 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction was quenched with water thennetraulized with saturated NaHCO₃ aqueous to pH 7. The resultingsolution was extracted with ^(i)PrOH/DCM. The organic layer was washedwith brine, dried over Na₂SO₄, and filtered then concentrate to give thetitle compound which was used in the next step without purification (350mg, 106% yield). LCMS m/z=348.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm1.58 (dd, J=13.64, 5.31 Hz, 1H), 1.61-1.70 (m, 1H), 1.76 (dt, J=17.43,14.15 Hz, 1H), 1.85 (dd, J=7.45, 4.42 Hz, 2H), 2.13 (dd, J=13.52, 7.96Hz, 1H), 2.76-2.90 (m, 2H), 3.45-3.56 (m, 3H), 3.63-3.71 (m, 1H), 3.85(dd, J=9.73, 5.68 Hz, 1H), 7.70 (dd, J=8.34, 4.29 Hz, 1H), 8.07 (dd,J=8.97, 2.15 Hz, 1H), 8.23 (d, J=8.84 Hz, 1H), 8.48 (d, J=2.02 Hz, 1H),8.58 (d, J=8.59 Hz, 1H), 9.04 (dd, J=4.29, 1.77 Hz, 1H).

Example 1.32 Preparation of Other Intermediates of the Present Invention

The following chemicals were prepared using similar methods to the onesdescribed in the above examples from proper intermediate(s) obtainedthrough commercial sources or synthesized according to literaturepreparation. The specific method(s) applicable were listed in thefollowing table:

Building LCMS Block Method of Data No. Chemical Structure Chemical NamePreparation [M + 1] C1

(S)-2-((3- (propylsulfonyl) phenoxy)methyl) oxirane BB1 257.4 C2

(S)-2-((3- ((cyclopropylmethyl) sulfonyl)phenoxy) methyl)oxirane BB1269.0 C3

(S)-2-((3- (isopropylsulfonyl) phenoxy)methyl) oxirane BB1 257.6 C4

(S)-2-((3-((3,3,3- trifluoropropyl) sulfonyl)phenoxy) methyl)oxirane BB1311.4 C5

(S)-2-((3- (isobutylsulfonyl) phenoxy)methyl) oxirane BB1 271.2 C6

(S)-2-((3- (isopentylsulfonyl) phenoxy)methyl) oxirane BB1 285.2 C7

2-((3-hydroxyphenyl) sulfonyl)acetonitrile BB1A BB1B BB1C 198.0 C8

3-((cyclobutylmethyl) sulfonyl)phenol BB1A BB1B BB1C 227.2 C9

3-((4,4,4- trifluorobutyl) sulfonyl)phenol BB1A BB1B BB1C 269.0 C10

(S)-2-((3- (ethylsulfonyl) phenoxy)methyl) oxirane BB1 243.2 C11

3-((cyclohexylmethyl) sulfonyl)phenol BB1A BB1B BB1C 255.4 C12

(2S)-2-((3-(((2,2- difluorocyclopropyl) methyl)sulfonyl) phenoxy)methyl)oxirane BB1 305.2 C13

(S)-2-((3- (cyclobutylsulfonyl) phenoxy)methyl) oxirane BB1 269.2 C14

3- (cyclopentylsulfonyl) phenol BB1A BB1B BB1C 227.2 C15

3-(benzylsulfonyl) phenol BB1A BB1B BB1C 249.0 C16

tert-butyl 3-((3- hydroxyphenyl) sulfonyl)azetidine-1- carboxylate BB1ABB1B BB1C 332.6 [M + 18]+ C17

tert-butyl (2-((3- hydroxyphenyl) sulfonyl)ethyl) carbamate BB1A BB1BBB1C 302.4 C18

(S)-2-((3- iodophenoxy)methyl) oxirane BB1D 277.0 C19

(2S)-2-((3-(sec- butylsulfonyl) phenoxy)methyl) oxirane BB1 271.2 C20

(S)-2-((3- ((fluoromethyl) sulfonyl)phenoxy) methyl)oxirane BB3 NA SeeNMR Below C21

(S)-2-((3- ((methylsulfonyl) methyl)phenoxy) methyl)oxirane BB1 NA SeeNMR Below C22

(S)-2-methyl-2-((3- (oxiran-2- ylmethoxy)phenyl) sulfonyl)propan-1-olDescribed in Example 1.29 287.0 C23

(S)-(1-((3-(oxiran-2- ylmethoxy)phenyl) sulfonyl)cyclobutyl) methanolDescribed in Example 1.28 299.4 C24

(S)-2-methyl-2-((3- (oxiran-2- ylmethoxy)phenyl) sulfonyl)propanamideBB5A BB5B BB1D 300.2 C25

(S)-3-((3-(oxiran-2- ylmethoxy)phenyl) sulfonyl)propan-1-ol BB1 273.2C26

(S)-2-((3- ((methoxymethyl)sul- fonyl)phenoxy)methyl) oxirane BB5 276.0[M + 18] C27

(S)-2-((3-((3- methoxypropyl) sulfonyl)phenoxy) methyl)oxirane BB5 287.0C28

(S)-3-((3-(oxiran-2- ylmethoxy)phenyl) sulfonyl)propanamide BB1 286.2C29

(S)-ethyl 2-methyl-2- ((3-(oxiran-2- ylmethoxy)phenyl)sulfonyl)propanoate BB5A BB5B BB1D 329.4 C30

(S)-3-((3-(oxiran-2- ylmethoxy)phenyl) sulfonyl)cyclobutanol BB3A BB1D285.2 C31

1H-pyrrolo[3,2- b]pyridine-6-sulfonyl chloride BB9 217.2 C32

(S)-2-((3-bromo-2- fluorophenoxy) methyl)oxirane BB1D 245.2 C33

(2S)-2-((3-((1- fluoroethyl)sulfonyl) phenoxy)methyl) oxirane BB6A BB6BBB6E BB1D 260.8 C34

(S)-2-03-fluoro-5- (oxiran-2- ylmethoxy)phenyl) sulfonyl)ethanol BB5BBB3A BB1D 277.2 C35

1H- benzo[d]imidazole-5- sulfonyl chloride BB9 217.0 C36

1,8-dimethyl-2,3- dihydro-1H- pyrido[2,3- b][1,4]oxazine-7- sulfonylchloride BB8C 263.2 C37

1,6-dimethyl-2,3- dihydro-1H- pyrido[2,3- b][1,4]oxazine-7- sulfonylchloride BB9 263.0 C38

1-ethy1-2,3-dihydro- 1H-pyrido[2,3- b][1,4]oxazine-7- sulfonyl chlorideBB9 263.2 C39

5-oxo-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridine-3-sulfonyl chloride BB9233.2 C40

2-oxo-2,3-dihydro- 1H-imidazo[4,5- b]pyridine-6-sulfonyl chloride BB9234.0 C41

5,6,7,8- tetrahydroquinoline-3- sulfonyl chloride BB9 232.2 C42

(S)-1,3-dimethy1-2,3- dihydro-1H- pyrido[2,3- b][1,4]oxazine-7- sulfonylchloride BB8C 263.0 C43

3,4-dihydro-2H- pyrano[2,3-b]pyridine- 6-sulfonyl chloride BB9 234.0 C44

2,3-dihydro- [1,4]dioxino[2,3- b]pyridine-7-sulfonyl chloride BB9 236.0C45

4-methyl-3,4-dihydro- 2H-pyrido[3,2- b][1,4]oxazine-7- sulfonyl chlorideBB9 249.2 C46

1,3,3-trimethyl-2,3- dihydro-1H- pyrido[2,3- b][1,4]oxazine-7- sulfonylchloride BB8C 277.2 C47

tert-butyl 7- (chlorosulfonyl)-2,3- dihydro-1H- pyrido[2,3-b][1,4]oxazine-1- carboxylate BB9 335.4 C48

(R)-1,3-dimethy1-2,3- dihydro-1H- pyrido[2,3- b][1,4]oxazine-7- sulfonylchloride BB8C 263.2 C49

1H-pyrrolo[2,3- b]pyridine-3-sulfonyl chloride BB9 217.2 C50

2-oxo-2,3-dihydro- 1H-pyrrolo[2,3- b]pyridine-5-sulfonyl chloride BB9233.2 C51

1H-pyrazolo[4,3- b]pyridine-6-sulfonyl chloride BB9 218.0 C52

8-fluoro-4- hydroxyquinoline-3- sulfonyl chloride BB12 261.9 C53

4-hydroxy-8- methylquinoline-3- sulfonyl chloride BB13 258.0 C54

3-(ethylsulfonyl) phenol BB1A BB1B BB1C 187.0 C55

tert-butyl 6- (chlorosulfonyl)-1H- pyrrolo[3,2- b]pyridine-1-carboxylate BB8C 317.0 C56

1-ethoxynaphthalene- 2-sulfonyl chloride BB9 270.8 C57

pyrrolo[1,2- a]pyrimidine-3- sulfonyl chloride BB9 216.8 C58

4-hydroxyquinoline-3- sulfonyl chloride A: STEP E 244.2 C59

1′-methyl-1′,2′- dihydrospiro [cyclopropane-1,3′- pyrido[2,3-b][1,4]oxazine]-7′- sulfonyl chloride BB8C 275.2 C60

4-hydroxy-6- methylquinoline-3- sulfonyl chloride BB13 258.1 C61

6-fluoro-4- hydroxyquinoline-3- sulfonyl chloride BB12 262.0 C62

3-(cyclobutylsulfonyl) phenol BB1A BB1B BB1C 213.0 C63

1-methyl-4-oxo-1,4- dihydroquinoline-3- sulfonyl chloride A: STEP D, E258.2

(S)-2-((3-((fluoromethyl)sulfonyl)phenoxy)methyl)oxirane (Building BlockNo. C20): ¹H NMR (400 MHz, CDCl₃) δ ppm 2.74 (dd, J=5.05, 2.78 Hz, 1H),2.86 (dd, J=5.05, 4.29 Hz, 1H), 3.36 (dddd, J=6.66, 4.39, 2.53, 2.34 Hz,1H), 3.96 (dd, J=11.37, 6.57 Hz, 1H), 4.48 (dd, J=11.37, 2.53 Hz, 1H),5.75 (d, J=45.73 Hz, 2H), 7.41-7.46 (m, 2H), 7.53 (ddd, J=7.71, 1.26,1.14 Hz, 1H), 7.64 (t, J=7.58 Hz, 1H).

(S)-2-((3-((methylsulfonyl)methyl)phenoxy)methyl)oxirane (Building BlockNo. C21): ¹H NMR (400 MHz, CDCl₃) δ ppm 2.75-2.79 (m, 4H), 2.92 (dd,J=4.8, 4.28 Hz, 1H), 3.36 (dddd, J=5.78, 4.20, 2.91, 2.78 Hz, 1H), 3.96(dd, J=11.12, 5.81 Hz, 1H), 4.22 (s, 2H), 4.29 (dd, J=11.12, 2.78 Hz,1H), 6.95-6.99 (m, 1H), 6.99-7.03 (m, 2H), 7.33 (t, J=8.08 Hz, 1H).

Example 1.33 Preparation of1-Ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 310) as the Mesylic Acid Salt. (Method A) Step A: Preparationof (R)-Benzyl 3-(((S)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

Into a solution of (S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane(11.26 g, 49.32 mmol) and (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (28.64 g, 98.63 mmol)in EtOH (978 mL) was bubbled with nitrogen for 1 h. The reaction washeated at 70° C. for 2 days. After cooling down to room temperature,solvent was removed under vacuum. The residue was dissolved in EtOAc(500 mL) and extracted with saturated NaHCO₃ aqueous solution. The EtOAclayer was separated. The aqueous layer was washed with EtOAc (1×). Thecombined organic layer was washed with water and brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel column chromatography to give the title compound (22.17 g, 87%yield). LCMS m/z=519.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.48-1.58(m, 1H), 1.58-1.77 (m, 4H), 2.12 (dd, J=12.88, 7.58 Hz, 1H), 2.71-2.82(m, 2H), 3.11 (s, 3H), 3.34-3.44 (m, 2H), 3.45-3.52 (m, 1H), 3.61-3.70(m, 3H), 3.96-4.14 (m, 4H), 5.11 (s, 2H), 7.26-7.33 (m, 2H), 7.34-7.37(m, 4H), 7.48-7.51 (m, 1H), 7.51-7.57 (m, 2H).

Step B: Preparation of (R)-Benzyl3-((tert-Butoxycarbonyl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of (R)-benzyl3-(((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(23.20 g, 44.73 mmol) in CH₂Cl₂ (300 mL) was added DIEA (23.37 mL, 134.2mmol) and (BOC)₂O (29.29 g, 134.2 mmol). The reaction was stirred undernitrogen at room temperature overnight. After the reaction wascompleted, the mixture was washed with saturated NH₄Cl aqueous solution,water, and then brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound (25.21 g, 91% yield).LCMS m/z=619.6 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.46 (s, 9H),1.48-1.57 (m, 1H), 1.60-1.74 (m, 3H), 1.89 (dd, J=12.76, 8.21 Hz, 1H),2.11 (dd, J=12.76, 8.46 Hz, 1H), 3.11 (s, 3H), 3.22-3.29 (m, 1H),3.34-3.46 (m, 2H), 3.56 (dd, J=14.53, 4.42 Hz, 1H), 3.60-3.71 (m, 2H),3.89-3.97 (m, 1H), 3.99-4.11 (m, 3H), 4.13-4.23 (m, 1H), 4.48-4.61 (m,1H), 5.11 (s, 2H), 7.25-7.38 (m, 6H), 7.50 (t, J=1.26 Hz, 1H), 7.51-7.59(m, 2H).

Step C: Preparation of tert-Butyl((S)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of (R)-benzyl3-((tert-butoxycarbonyl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(20.8 g, 33.62 mmol) in MeOH (336.2 mL) under H₂ balloon was addedPalladium/C (3.59 g, 3.36 mmol). The reaction was stirred at roomtemperature. After the reaction was completed, the mixture was filteredthrough a pad of Celite® then washed with MeOH. The filtrate wasconcentrated to give the title compound (15.43 g, 88% yield) as a whitefoam. LCMS m/z=485.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38 (s,9H), 1.41 (d, J=6.82 Hz, 2H), 1.49-1.58 (m, 2H), 1.66 (dd, J=12.38, 8.59Hz, 1H), 2.01 (dd, J=12.38, 8.34 Hz, 1H), 2.52-2.58 (m, 1H), 2.71-2.84(m, 2H), 3.01-3.13 (m, 1H), 3.21 (s, 3H), 3.42 (dd, J=14.27, 4.17 Hz,1H), 3.75-3.89 (m, 2H), 3.92-4.11 (m, 3H), 4.44 (bs, 1H), 5.25 (d,J=3.79 Hz, 1H), 7.27 (dd, J=8.21, 1.64 Hz, 1H), 7.41 (t, J=2.02 Hz, 1H),7.49 (d, J=7.83 Hz, 1H), 7.57 (t, J=7.96 Hz, 1H).

Step D: Preparation of 1-Ethylquinolin-4(1H)-one

To a solution of quinolin-4-ol (25 g, 172.2 mmol) in DMF (100 mL) wasadded potassium carbonate (47.61 g, 344.5 mmol). The reaction wasstirred at room temperature for 30 min. Bromoethane (17.87 mL, 241.1mmol) was added. The reaction mixture was heated to 80° C. overnight.After the reaction was completed and cooled down to room temperature,the mixture was filtered through a pad of celite and washed with DCM.The filtrate was concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound (13.65 g, 46% yield) asa yellow solid. LCMS m/z=174.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.34 (t, J=7.07 Hz, 3H), 4.28 (q, J=7.16 Hz, 2H), 6.05 (d, J=7.58 Hz,1H), 7.37 (ddd, J=7.96, 4.93, 3.03 Hz, 1H), 7.69-7.76 (m, 2H), 7.99 (d,J=7.58 Hz, 1H), 8.19 (d, J=7.83 Hz, 1H).

Step E: Preparation of 1-Ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonylChloride

Freshly distilled sulfurochloridic acid (9.21 mL, 138.6 mmol) was addeddrop wise under N₂ into a 3 necks round bottom flask containing1-ethylquinolin-4(1H)-one (4 g, 23.09 mmol) until the bubbles sloweddown. (Note: A lot of smoke formed and gas evolved.) The resulting clearbrown solution was stirred at room temperature for 30 min and thenheated at 100° C. under N₂ overnight. The reaction was cooled down toroom temperature. The mixture was slowly poured into crushed ice in a500 mL beaker with vigorously stirring. The precipitate was filtered andwashed with cold water to give the title compound (3.86 g, 54% yield) asa beige solid. LCMS m/z=271.8 [M]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46(t, J=7.07 Hz, 3H), 4.76 (q, J=7.07 Hz, 2H), 7.79 (t, J=7.58 Hz, 1H),8.08 (dd, J=15.66, 1.52 Hz, 1H), 8.22 (d, J=8.84 Hz, 1H), 8.43 (dd,J=8.34, 1.52 Hz, 1H), 9.26 (s, 1H).

Step F: Preparation of tert-Butyl((R)-8-((1-Ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(15.51 g, 32.01 mmol) in CH₂Cl₂ (160 mL) were added DIEA (12.94 mL,74.18 mmol) and 1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride(85.4% pure, 12.07 g, 37.94 mmol). The reaction was stirred at roomtemperature for 4 h, then quenched with water, and washed with 10% ofIPA/DCM. The aqueous layer was back extracted with IPA/DCM (10%). Thecombined organic layer was dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound (21.2 g, 82% yield) as a white foam. LCMS m/z=720.6[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36 (s, 9H), 1.37-1.42 (m, 3H),1.47-1.57 (m, 1H), 1.58-1.76 (m, 4H), 2.98-3.17 (m, 3H), 3.19 (s, 3H),3.35 (d, J=4.04 Hz, 1H), 3.41 (dd, J=14.27, 3.92 Hz, 1H), 3.77 (t,J=8.21 Hz, 1H), 3.84 (d, J=7.07 Hz, 1H), 3.89-4.06 (m, 4H), 4.45 (q,J=7.07 Hz, 3H), 5.22 (d, J=5.05 Hz, 1H), 7.25 (ddd, J=6.82, 1.52, 1.26Hz, 1H), 7.39 (d, J=2.53 Hz, 1H), 7.44-7.49 (m, 1H), 7.50-7.58 (m, 2H),7.86 (d, J=1.26 Hz, 2H), 8.26 (d, J=7.58 Hz, 1H), 8.61 (s, 1H).

Step G: Preparation of1-Ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 310) as the Mesylic Acid Salt

A solution of tert-butyl((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate(17.42 g, 24.19 mmol) in acetone (78.81 mL) was prepared in a 500 mLround bottom flask assembled with a condenser and a needle outlet septumto give a clear light yellow solution. The resulting solution was heatedto 60° C. Methanesulfonic acid (2.02 mL, 31.45 mmol) was added drop wiseinto the reaction solution stirred vigorously. After 1 h of stirring,white precipitation formed; a seed crystal of mesylate salt of the titlecompound (15 mg) was added into the reaction mixture. After adding theseed crystal, there was more precipitation formed within 20 minutes. Thestir bar stopped moving. The precipitated cake was broken by a spatulaand more acetone (84 mL) was added. Heating was continued overnight withstirring. Heating was turned off next day. The reaction mixture wasstirred at room temperature overnight. Next day, the reaction wasreheated up to 60° C. with stirring for 1 h then precipitation wascollected via vacuum filtration while still hot. The cake was washedwith acetone (3×100 mL) at room temperature and dried under heatedvacuum oven at 50° C. to give the tile compound (15.24 g, 88% yield) asa white solid. LCMS m/z=620.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.38 (t, J=7.07 Hz, 3H), 1.51-1.61 (m, 1H), 1.62-1.71 (m, 1H), 1.71-1.82(m, 3H), 2.20 (dd, J=13.26, 8.21 Hz, 1H), 2.30 (s, 3H), 2.94-3.05 (m,1H), 3.06-3.20 (m, 3H), 3.21 (s, 3H), 3.30-3.43 (m, 1H), 3.76-3.85 (m,1H), 3.90-3.99 (m, 2H), 4.07 (d, J=5.05 Hz, 2H), 4.10-4.19 (m, 1H), 4.46(q, J=7.07 Hz, 2H), 5.91 (bs, 1H), 7.30 (ddd, J=8.15, 2.46, 0.76 Hz,1H), 7.44 (t, J=2.27 Hz, 1H), 7.50-7.56 (m, 2H), 7.59 (t, J=7.96 Hz,1H), 7.82-7.91 (m, 2H), 8.25 (dd, J=7.83, 1.26 Hz, 1H), 8.63 (s, 1H),8.76 (bs, 2H). ¹³C NMR (400 MHz, DMSO-d₆) δ ppm 14.30, 35.68, 36.35,42.54, 43.10, 43.21, 43.35, 48.09, 50.44, 58.11, 67.65, 70.45, 71.00,78.90, 112.31, 117.02, 117.43, 118.81, 120.05, 125.12, 126.17, 127.71,130.58, 133.31, 138.91, 142.03, 147.53, 158.91, 171.53.

Example 1.34 Preparation of(S)-1-(3-(2-Hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 88). (Method B) Step A: Preparation of (R)-tert-Butyl1-Oxa-8-azaspiro[4.5]decan-3-ylcarbamate

To a solution of (R)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(39.8 g, 101.9 mmol) in MeOH (254.8 mL) under H₂ balloon was addedPalladium/C (10.85 g, 10.19 mmol) at room temperature. The reaction wasstirred at room temperature overnight. After the reaction was completed,the mixture was filtered through a pad of Celite®, washed with MeOH, andconcentrated. The residue was triturated with EtOAc/Hex (10%) to givethe title compound (21.02 g, 80% yield) as a yellow gum. LCMS m/z=257.4[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37 (s, 9H), 1.41 (t, J=5.68Hz, 2H), 1.52 (dd, J=6.69, 3.41 Hz, 3H), 1.96 (dd, J=12.63, 8.34 Hz,1H), 2.52-2.58 (m, 2H), 2.72-2.84 (m, 2H), 3.41 (dd, J=8.59, 6.57 Hz,1H), 3.83 (dd, J=8.59, 6.82 Hz, 1H), 3.92-4.08 (m, 1H), 6.99 (bs, 1H).

Step B: Preparation of (R)-tert-Butyl(8-(Quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of (R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate(21.02 g, 82.00 mmol) in CH₂Cl₂ (370 mL) under nitrogen was added DIEA(14.28 mL, 82.00 mmol) at 0° C. followed by addition of aquinoline-3-sulfonyl chloride (20.54 g, 90.20 mmol) solution in CH₂Cl₂via addition funnel. The reaction mixture was slowly warmed up to roomtemperature overnight. After the reaction was completed, the mixture waswashed with water and then brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated. The residue was triturated withhexane to give the title compound (42.31 g, 112% yield) as a lightyellow solid. LCMS m/z=448.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.34 (s, 9H), 1.53 (dd, J=13.01, 6.44 Hz, 1H), 1.62 (t, J=4.29 Hz, 2H),1.71 (t, J=4.55 Hz, 2H), 1.91 (dd, J=12.88, 8.34 Hz, 1H), 2.65-2.83 (m,2H), 3.31-3.39 (m, 2H), 3.72 (dd, J=8.84, 6.57 Hz, 1H), 3.87-4.01 (m,1H), 6.99 (d, J=5.81 Hz, 1H), 7.81 (ddd, J=8.15, 7.01, 1.01 Hz, 1H),8.00 (ddd, J=8.46, 6.95, 1.52 Hz, 1H), 8.17 (d, J=8.34 Hz, 1H), 8.29 (d,J=7.58 Hz, 1H), 8.92 (d, J=1.77 Hz, 1H), 9.13 (d, J=2.27 Hz, 1H).

Step C: Preparation of(R)-8-(Quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine

To a solution of (R)-tert-butyl(8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(42.52 g, 95.01 mmol) in CH₂Cl₂ (237.5 mL) was slowly added TFA (79 mL,1.032 mol) at 0° C. The reaction was stirred at room temperature for 2.5h. After the reaction was completed, the mixture was concentrated. Thereddish brown oil residue was triturated with MTBE to give the titlecompound (30.34 g, 92% yield) as a light brown solid. LCMS m/z=348.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.45 (dd, J=13.01, 5.68 Hz, 1H),1.53-1.67 (m, 2H), 1.70-1.84 (m, 2H), 1.94 (dd, J=13.01, 7.71 Hz, 1H),2.65-2.80 (m, 2H), 3.16-3.45 (m, 3H), 3.53 (dq, J=7.71, 5.68 Hz, 1H),3.69 (dd, J=9.09, 6.06 Hz, 1H), 7.81 (td, J=7.58, 1.01 Hz, 1H), 8.00(td, J=8.46, 6.95, 1.52 Hz, 1H), 8.18 (d, J=8.59 Hz, 1H), 8.28 (d,J=1.01 Hz, 1H), 8.93 (d, J=2.02 Hz, 1H), 9.13 (d, J=2.27 Hz, 1H).

Step D: Preparation of(S)-1-(3-(2-Hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 88). (Method BD)

A solution of (S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol(15.23 g, 38.91 mmol) and(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (27.04g, 77.82 mmol) in EtOH (160 mL) was heated at 70° C. for 24 h. After thereaction was completed, the mixture was concentrated. The residue waspurified by prep-HPLC. The fractions were combined and neutralized withsaturated NaHCO₃ aqueous solution. The volatile was evaporated, and thenthe aqueous layer was extracted with IPA/CH₂Cl₂ (10%). The organic layerwas dried over Na₂SO₄, filtered, and concentrated to give the titlecompound (9.70 g, 41% yield) as a white solid. LCMS m/z=606.4 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.46 (dd, J=12.63 5.31 Hz, 1H), 1.60 (t,J=5.68 Hz, 2H), 1.65-1.81 (m, 2H), 1.88 (dd, J=12.25, 7.20 Hz, 1H),2.53-2.61 (m, 2H), 2.68-2.79 (m, 2H), 3.32-3.40 (m, 3H), 3.44 (t, J=6.44Hz, 2H), 3.62-3.73 (m, 3H), 3.78-3.86 (m, 1H), 3.89-3.95 (m, 1H),3.98-4.04 (m, 1H), 4.86 (t, J=5.56 Hz, 1H), 5.02 (bs, 1H), 7.25 (ddd,J=8.21, 2.53, 0.88 Hz, 1H), 7.36 (t, J=2.53 Hz, 1H), 7.43 (dd, J=8.34,1.77 Hz, 1H), 7.52 (t, J=7.96 Hz, 1H), 7.81 (ddd, J=8.15, 7.01, 1.01 Hz,1H), 8.00 (ddd, J=8.46, 6.95, 1.52 Hz, 1H), 8.18 (d, J=8.34 Hz, 1H),8.29 (dd, J=8.46, 0.88 Hz, 1H), 8.92 (d, J=1.77 Hz, 1H), 9.13 (d, J=2.27Hz, 1H).

Example 1.35 Preparation of(2S)-1-(4-(Methylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 334). (Method C) Step A: Preparation of tert-Butyl(8-(Naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

Benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(4.1 g, 10.50 mmol) was dissolved in MeOH (15 mL). Palladium/C (0.11 g,1.05 mmol) and a double balloon of hydrogen (gas) were applied. Thereaction was vigorously stirred at room temperature for 2 h. After thistime, the reaction was complete. The reaction was filtered through aplug of celite. The solvent was completely removed. The resultingviscous oil was re-dissolved in CH₂Cl₂ (30 mL). DIEA (2.74 mL, 15.75mmol) was added, followed by naphthalene-2-sulfonyl chloride (2.62 g,11.55 mmol) (a slightly exothermic reaction, and bubbling, took place).The reaction was stirred at room temperature for a half hour. After thistime, the reaction was complete. The solvent was removed, and theresidue was purified by silica gel column chromatography to give thetitle compound (4.5 g, 95.0% yield) as a white solid. LCMS m/z=447.6[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s, 9H), 1.48-1.56 (m, 1H),1.56-1.63 (m, 2H), 1.64-1.74 (m, 2H), 1.85-1.94 (m, 1H), 2.59-2.72 (m,2H), 3.25-3.33 (m, 3H), 3.67-3.75 (m, 1H), 3.88-3.99 (m, 1H), 6.97 (d,J=8.7 Hz, 1H), 7.67-7.79 (m, 3H), 8.08 (d, J=8.0 Hz, 1H), 8.17 (d, J=8.7Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.42 (d, J=1.4 Hz, 1H).

Step B: Preparation of tert-Butyl(8-(Naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-oxiran-2-ylmethyl)carbamate

tert-Butyl(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(2.0 g, 4.48 mmol) was dissolved in DMF (6 mL; the solution remainedslightly cloudy). Sodium Hydride (0.32 g, 13.44 mmol) was added at roomtemperature (bubbling was observed). The reaction was stirred at roomtemperature for a half hour. Then, (S)-2-(chloromethyl)oxirane (2.07 g,22.39 mmol) was added to the stirring solution. The reaction was stirredat room temperature for an hour. After this time, the reaction wasaround 50% complete by TLC analysis. The reaction was warmed in an oilbath to 40° C., and stirred at this temperature for 2 h. After thistime, the starting material was consumed. The reaction was cooled anddiluted with EtOAc (20 mL). The reaction was poured into a separatoryfunnel with H₂O (30 mL), and extracted with EtOAc. The combined organiclayer was dried, concentrated, and the residue was purified by silicagel column chromatography to give the title compound (1.47 g, 2.63 mmol,58.8% yield) as a white foamy solid. LCMS m/z=503.6 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.37 (s, 9H), 1.50-1.81 (m, 5H), 1.88-1.99 (m, 1H),2.41-2.48 (m, 1H), 2.57-2.75 (m, 3H), 2.92-3.00 (m, 1H), 3.23-3.43 (m,3H), 3.43-3.50 (m, 1H), 3.52-3.59 (m, 1H), 3.63-3.73 (m, 1H), 4.35-4.51(m, 1H), 7.66-7.79 (m, 3H), 8.09 (d, J=7.9 Hz, 1H), 8.17 (d, J=8.8 Hz,1H), 8.21 (d, J=8.0 Hz, 1H), 8.43 (s, 1H).

Step C: Preparation of(2S)-1-(4-(Methylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 334)

tert-Butyl(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-oxiran-2-ylmethyl)carbamate(10 mg, 19.90 μmol), 4-(methylsulfonyl)phenol (4.11 mg, 23.87 μmol), andpotassium carbonate (8.25 mg, 59.69 μmol) were dissolved/suspended inDMF (0.2 mL). The reaction was heated to 100° C. overnight. The mixturewas filtered through a plug of Celite®. The filtrate was concentratedand purified by Prep LC/MS to give tert-butyl((S)-2-hydroxy-3-(4-(methylsulfonyl)phenoxy)propyl)(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate.After lyophilizing, the material was dissolved in ACN (1.5 mL). 4N HClin dioxane (100 μl, 0.400 mmol) was added, and the reaction was allowedto stand until the Boc-group was completely cleaved. The solvents wereremoved completely, and the resulting material was dissolved in ACN (0.2mL) and H₂O (0.5 mL), frozen, and lyophilized again to give the HCl saltof the title compound. Due to the presence of an impurity observed inthe LC/MS after the lyophilized step, the material was again purified byPrep LC/MS to give the title compound (3.3 mg, 23.8% yield) as a whitesolid (TFA salt). LCMS m/z=575.4 [M+H]⁺.

Example 1.36 Preparation of(2S)-1-(3-(Ethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 15) Step A: Preparation of tert-Butyl(8-(Naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-oxiran-2-ylmethyl)carbamate

tert-Butyl(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(1.5 g, 3.36 mmol)) was dissolved anhydrous DMF (12 mL) under N₂ to givea clear colorless solution. Sodium hydride (0.61 g, 15.12 mmol) wasadded. The grayish suspension was stirred at room temperature for 30 minfollowed by addition of (S)-2-(chloromethyl)oxirane (1.32 mL, 16.80mmol). The reaction was stirred at room temperature under N₂ for 2 h.The reaction was quenched with water, then poured into a saturatedNaHCO₃ aqueous solution (25 mL). The resulting mixture was extractedwith EtOAc (3×). The combined organic layer was washed with water andbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by silica gel column chromatography to the title compound (323mg, 22% yield). LCMS m/z=503.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm1.44 (s, 9H), 1.56-1.69 (m, 1H), 1.69-1.88 (m, 4H), 1.97-2.05 (m, 1H),2.50 (dt, J=4.80, 2.40 Hz, 1H), 2.72-2.77 (m, 1H), 2.77-2.88 (m, 2H),2.98-3.07 (m, 1H), 3.32-3.38 (m, 2H), 3.38-3.50 (m, 2H), 3.56 (dd,J=14.78, 1.89 Hz, 1H), 3.70-3.81 (m, 1H), 4.49 (bs, 1H), 7.63-7.73 (m,2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8.08 (d,J=8.34 Hz, 2H), 8.37 (d, J=1.26 Hz, 1H).

Step B: Preparation of(2S)-1-(3-(Ethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 15)

A solution of tert-butyl(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-oxiran-2-ylmethyl)carbamate(15 mg, 29.84 μmol) in DMF (0.2 mL) was added into a 5 mL scintillationvial containing 3-(ethylsulfonyl)phenol (10.28 mg, 59.69 μmol) and K₂CO₃(12.37 mg, 89.53 μmol). The reaction was heated at 70° C. overnight.After the reaction was completed, the mixture was filtered through a padof Celite® then concentrated. The residue was purified by mass directedprep-HPLC to give tert-butyl((S)-2-hydroxy-3-(3-(ethylsulfonyl)phenoxy)propyl)(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate.LCMS m/z=689.4 [M+H]⁺.

To a solution of tert-butyl((S)-2-hydroxy-3-(3-(ethylsulfonyl)phenoxy)propyl)(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamatein ACN (2 mL) was added 4N HCl (in Dioxane, 75 μL, 0.30 mmol). Thereaction was gently shaken for 2 h at room temperature and concentrated.The residue was purified by mass directed prep-HPLC to give the titlecompound (8.1 mg, 39% yield) as an off white solid. LCMS m/z=589.4[M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.20 (t, J=8.00 Hz, 3H), 1.67 (dd,J=10.86, 4.29 Hz, 1H), 1.75-1.96 (m, 4H), 2.28 (ddd, J=13.58, 8.02, 2.40Hz, 1H), 2.73-2.90 (m, 2H), 3.06-3.29 (m, 4H), 3.49 (t, J=12.63 Hz, 2H),3.79-3.88 (m, 1H), 3.92-4.03 (m, 2H), 4.04-4.13 (m, 2H), 4.18-4.27 (m,1H), 7.29 (ddd, J=8.08, 2.53, 1.26 Hz, 1H), 7.44 (t, J=4.00 Hz, 1H),7.48-7.52 (m, 1H), 7.55 (t, J=8.00 Hz, 1H), 7.68 (qd, J=8.25, 8.08 Hz,2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8.08 (d,J=8.84 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Example 1.37 Preparation of(2S)-1-(3-(Methylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 1). (Method D)

(S)-2-((3-(Methylsulfonyl)phenoxy)methyl)oxirane (20 mg, 87.62 nmol) and8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (33.39mg, 96.38 nmol, prepared from benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylateusing a similar method to the one described in Example 1.2, Step A andB) were dissolved in EtOH (2.5 mL). The reaction was heated at 60° C.overnight. After the reaction was completed and cooled down to roomtemperature, it was concentrated and purified by mass direct prep-HPLCto give the title compound (7 mg, 12% yield). LCMS m/z=575.4 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ ppm 1.31-1.38 (m, 1H), 1.61-1.72 (m, 1H),1.77-1.96 (m, 4H), 2.29 (dd, J=13.77, 8.21 Hz, 1H), 2.74-2.91 (m, 2H),3.10 (s, 3H), 3.44-3.55 (m, 4H), 3.79-3.87 (m, 1H), 3.93-4.03 (m, 2H),4.09 (d, J=4.80 Hz, 2H), 4.20-4.29 (m, 1H), 7.26-7.33 (m, 1H), 7.49 (s,1H), 7.55 (d, J=5.05 Hz, 2H), 7.62-7.74 (m, 2H), 7.77 (d, J=8.59 Hz,1H), 8.01 (d, J=8.08 Hz, 1H), 8.09 (d, J=8.59 Hz, 2H), 8.38 (s, 1H).

Example 1.38 Preparation of(S)-1-(3-(Cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 154). (Method E) Step A: Preparation of (R)-Benzyl3-((tert-butoxycarbonyl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

A solution of (S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane(7.63 g, 30.00 mmol) and (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (17.42 g, 60.01 mmol)in EtOH (150 mL) was heated at 70° C. overnight. After the reaction wascompleted, the mixture was concentrated. The residue was purified bysilica gel column chromatography to give (R)-benzyl3-(((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(6.34 g, 61% yield). LCMS m/z=545.6 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δppm 1.00-1.09 (m, 2H), 1.32-1.39 (m, 2H), 1.46-1.58 (m, 1H), 1.60-1.74(m, 2H), 1.79 (dd, J=13.14, 5.81 Hz, 2H), 2.10-2.17 (m, 1H), 2.48 (tt,J=7.96, 4.93 Hz, 1H), 2.92-3.09 (m, 2H), 3.35 (q, J=10.78 Hz, 2H),3.61-3.70 (m, 1H), 3.70-3.81 (m, 2H), 3.84-3.92 (m, 1H), 4.01-4.14 (m,3H), 4.21-4.31 (m, 1H), 5.13 (s, 2H), 7.17 (ddd, J=7.89, 2.46, 1.26 Hz,1H), 7.28-7.39 (m, 5H), 7.40-7.55 (m, 3H).

To a solution of (R)-benzyl3-(((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(6.34 g, 11.63 mmol) in CH₂Cl₂ (150.0 mL) was added DIEA (3.7 mL, 21.2mmol) and (BOC)₂O (4.4 g, 20.2 mmol). The reaction was stirred at roomtemperature overnight. After the reaction was completed, the mixture wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (5.81 g). LCMS m/z=645.4[M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.00-1.08 (m, 2H), 1.31-1.39 (m,2H), 1.50 (s, 10H), 1.63-1.76 (m, 3H), 1.82 (dd, J=13.01, 8.21 Hz, 1H),2.09 (dd, J=12.88, 8.59 Hz, 1H), 2.41-2.52 (m, 1H), 3.27-3.54 (m, 4H),3.66-3.79 (m, 2H), 3.80-3.90 (m, 1H), 3.92-4.07 (m, 3H), 4.11-4.20 (m,1H), 4.57-4.69 (m, 1H), 5.14 (s, 2H), 7.16 (ddd, J=8.02, 2.59, 1.26 Hz,1H), 7.29-7.40 (m, 5H), 7.42 (t, J=2.27 Hz, 1H), 7.45-7.54 (m, 2H).

Step B: Preparation of tert-Butyl((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of (R)-benzyl3-((tert-butoxycarbonyl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(5.80 g, 9.00 mmol) in MeOH (45 mL) under nitrogen was added palladium/C(0.96 g, 0.90 mmol). The reaction was stirred at room temperatureovernight under H₂ balloons. After the reaction was completed, themixture was filtered through a pad of Celite® and washed with MeOH. Thefiltrate was concentrated to give the title compound (4.6 g, 100% yield)as a white foam LCMS m/z=511.6 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm1.00-1.09 (m, 2H), 1.32-1.38 (m, 2H), 1.50 (s, 9H), 1.56-1.80 (m, 6H),2.13 (dd, J=12.88, 8.84 Hz, 1H), 2.46 (tt, J=7.96, 4.80 Hz, 1H),2.71-2.81 (m, 2H), 2.93-3.07 (m, 2H), 3.38-3.56 (m, 2H), 3.76-3.87 (m,1H), 3.93-4.07 (m, 3H), 4.12-4.20 (m, 1H), 4.59-4.71 (m, 1H), 7.16 (ddd,J=7.83, 2.53, 1.52 Hz, 1H), 7.42 (t, J=1.52 Hz, 1H), 7.45-7.55 (m, 2H).

Step C: Preparation of tert-Butyl((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(1.96 g, 3.84 mmol) in CH₂Cl₂ (19.18 mL) was added DIEA (0.80 mL, 4.60mmol) and 1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonylchloride (1.10 g, 4.41 mmol). The reaction was stirred at roomtemperature overnight. After the reaction was completed, the mixture wasconcentrated. The residue was then purified by silica gel columnchromatography to give the title compound (2.5 g, 90% yield). LCMSm/z=723.6 [M+H]⁺.

Step D: Preparation of(S)-1-(3-(Cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (Compound 154)

To a solution of tert-Butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(2.5 g, 3.46 mmol) in DCM (19 mL) was added TFA (7 mL, 91.41 mmol). Thereaction was stirred at room temperature for 1 h. The mixture wasconcentrated. The residue was diluted with water. The mixture wasneutralized with saturated NaHCO₃ aqueous solution then extracted withIPA/DCM (10%). The organic layer was washed with water and brine, thendried over Na₂SO₄, and filtered. The filtrate was concentrated to givethe title compound (2.1 g, 88% yield) as a foam. LCMS m/z=623.4 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.07 (m, 2H), 1.09-1.13 (m, 2H),1.47 (dd, J=12.76, 5.43 Hz, 1H), 1.56-1.61 (m, 2H), 1.67 (dd, J=10.61,4.29 Hz, 1H), 1.72-1.80 (m, 1H), 1.89 (dd, J=12.76, 7.45 Hz, 1H),2.53-2.68 (m, 4H), 2.87 (dd, J=12.63, 3.03 Hz, 1H), 2.91 (s, 3H), 3.23(dd, J=10.74, 5.94 Hz, 2H), 3.33-3.43 (m, 4H), 3.75 (dd, J=8.59, 5.81Hz, 1H), 3.80-3.88 (m, 1H), 3.91-3.98 (m, 1H), 4.02-4.07 (m, 1H), 4.45(t, J=4.8 Hz, 2H), 4.96-5.06 (m, 1H), 7.02 (d, J=2.27 Hz, 1H), 7.28 (dd,J=7.83, 2.02 Hz, 1H), 7.35 (t, J=1.77 Hz, 1H), 7.43 (d, J=8.34 Hz, 1H),7.55 (t, J=7.96 Hz, 1H), 7.71 (d, J=2.02 Hz, 1H). ¹³C NMR (400 MHz,CD₃OD) δ ppm 6.51, 25.39, 33.55, 35.28, 36.97, 38.42, 41.06, 44.42,44.81, 48.12, 50.51, 59.71, 66.69, 67.80, 68.45, 71.71, 80.99, 114.62,117.44, 121.12, 121.26, 129.23, 131.54, 132.03, 135.13, 143.44, 154.96,160.46.

Example 1.39 Preparation of3-((R)-3-((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethylquinolin-4(1H)-one(Compound 297) Step A: Preparation of tert-Butyl((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(294 mg, 0.58 mmol) in CH₂Cl₂ (5 mL) was added DIEA (0.22 mL, 1.26 mmol)followed by 1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride (0.27g, 0.98 mmol). The reaction was stirred at room temperature overnight.The mixture was concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound. LCMS m/z=746.4 [M+H]⁺.

Step B: Preparation of3-((R)-3-((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethylquinolin-4(1H)-one(Compound 297)

tert-Butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(from the previous Step) was stirred in TFA/DCM (14%, 5 mL) at roomtemperature overnight. The mixture was concentrated and the residue waspurified by prep-HPLC. The combined fractions were neutralized withaqueous NaHCO₃ then MeCN was removed under pressure. The aqueous layerwas extracted with IPA/DCM (10%, 2×150 mL). The combined organic layerwas washed with brine, then dried over Na₂SO₄, filtered andconcentrated. The residue was dissolved in ACN (14 mL) then HCl (4N indioxane, 2.3 equiv.) was added. The solution was stirred at roomtemperature for 1 h followed by addition of water (21 mL). The mixturewas then lyophilized to give the title compound (356 mg, 86% yield).LCMS m/z=646.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.08 (m,2H), 1.08-1.15 (m, 2H), 1.38 (t, J=7.07 Hz, 3H), 1.51-1.60 (m, 1H),1.62-1.70 (m, 1H), 1.72-1.84 (m, 3H), 2.20 (dd, J=13.39, 8.08 Hz, 1H),2.87 (tt, J=7.80, 4.83 Hz, 1H), 2.93-3.04 (m, 1H), 3.05-3.22 (m, 3H),3.29-3.42 (m, 2H), 3.78-3.87 (m, 1H), 3.87-3.99 (m, 2H), 4.07 (d, J=5.05Hz, 2H), 4.14-4.23 (m, 1H), 4.46 (q, J=7.07 Hz, 2H), 7.31 (dd, J=8.08,1.77 Hz, 1H), 7.38 (t, J=1.77 Hz, 1H), 7.48 (d, J=7.83 Hz, 1H), 7.53(ddd, J=7.96, 6.32, 1.64 Hz, 1H), 7.58 (t, J=7.96 Hz, 1H), 7.82-7.92 (m,2H), 8.24 (d, J=1.26 Hz, 1H), 8.63 (s, 1H), 8.96 (bs, 1H), 9.09 (bs,1H).

Example 1.40 Preparation of2-(3-((S)-2-Hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)acetamide(Compound 123). (Method E2) Step A: Preparation of (R)-Benzyl3-(((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

A solution of (S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)acetamide(14.75 g, 54.38 mmol) and (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (62.5 g, 98.8 mmol) inEtOH (550 mL) was heated at 70° C. for 40 h. After the reaction wascompleted and cooled down to room temperature, the mixture wasconcentrated. The residue was used in the next step withoutpurification. LCMS m/z=562.4 [M+H]⁺.

Step B: Preparation of (R)-Benzyl3-(((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)(tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

(R)-benzyl3-(((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylatefrom the previous step was dissolved in CH₂Cl₂ (550 mL) then cooled downto 0° C. DIEA (37.89 mL, 217.5 mmol) and (BOC)₂O (71.21 g, 326.3 mmol)were added. The reaction was stirred at room temperature. The mixturewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound (22.1 g, 61% yield) as ayellow foam. LCMS m/z=662.6 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.50(s, 10H), 1.64-1.85 (m, 4H), 2.09 (dd, J=13.14, 8.84 Hz, 1H), 3.29-3.55(m, 4H), 3.68-3.87 (m, 3H), 3.92-4.01 (m, 4H), 4.02-4.08 (m, 1H),4.11-4.19 (m, 1H), 4.61-4.71 (m, 1H), 5.13 (s, 2H), 5.58-5.93 (m, 1H),6.62-6.73 (m, 1H), 7.21 (ddd, J=7.83, 2.53, 1.52 Hz, 1H), 7.30-7.39 (m,5H), 7.43 (t, J=1.77 Hz, 1H), 7.48-7.58 (m, 2H).

Step C: Preparation of tert-Butyl((S)-3-(3-((2-Amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of (R)-benzyl3-(((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)(tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(22.1 g, 32.40 mmol) in MeOH (324 mL) under N₂ was added Palladium/C(3.45 g, 3.24 mmol). The reaction was stirred overnight under H₂balloons. The mixture was passed through a pad of Celite® and washedwith MeOH. The filtrate was concentrated to give the title compound(17.6 g, 103% yield) as a white foam which was used in the next stepwithout purification. LCMS m/z=528.6 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δppm 1.50 (s, 9H), 1.54-1.69 (m, 2H), 1.71-1.83 (m, 3H), 2.10 (dd,J=13.01, 8.97 Hz, 1H), 2.72-2.88 (m, 2H), 3.00 (dddd, J=17.27, 8.56,8.40, 4.17 Hz, 2H), 3.38-3.56 (m, 2H), 3.66-3.85 (m, 1H), 3.92-4.09 (m,5H), 4.10-4.18 (m, 1H), 4.58-4.73 (m, 1H), 6.19-6.51 (m, 1H), 6.75 (bs,1H), 7.22 (dd, J=7.58, 2.53 Hz, 1H), 7.44 (t, J=1.77 Hz, 1H), 7.48-7.58(m, 2H).

Step D: Preparation of tert-Butyl((S)-3-(3-((2-Amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of tert-butyl((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(15.93 g, 30.20 mmol) in CH₂Cl₂ (151 mL) under nitrogen were added DIEA(7.89 mL, 45.29 mmol) and quinoline-3-sulfonyl chloride (8.25 g, 36.23mmol) portion wise at room temperature. The reaction was stirred for 1h. The mixture was concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound (18.89 g, 87% yield) asa light yellow foam. LCMS m/z=719.4 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δppm 1.47 (s, 9H), 1.56-1.73 (m, 1H), 1.75-1.84 (m, 2H), 1.85-1.94 (m,2H), 2.05 (dd, J=13.14, 8.84 Hz, 1H), 2.75-2.90 (m, 2H), 3.30-3.42 (m,1H), 3.42-3.49 (m, 1H), 3.56-3.76 (m, 3H), 3.77-3.84 (m, 1H), 3.88-3.96(m, 1H), 3.97-4.04 (m, 3H), 4.07-4.15 (m, 1H), 4.58 (quin, J=7.52 Hz,1H), 5.81 (bs, 1H), 6.75 (bs, 1H), 7.18 (ddd, J=7.83, 2.65, 1.39 Hz,1H), 7.39 (t, J=2.27 Hz, 1H), 7.47-7.57 (m, 2H), 7.71 (ddd, J=8.15,7.01, 1.26 Hz, 1H), 7.91 (ddd, J=8.53, 7.01, 1.39 Hz, 1H), 7.99 (d,J=8.34 Hz, 1H), 8.22 (d, J=8.34 Hz, 1H), 8.65 (d, J=1.77 Hz, 1H), 9.20(d, J=2.27 Hz, 1H).

Step E: Preparation of2-(3-((S)-2-Hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)acetamide(Compound 123)

tert-Butyl((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamatefrom the previous step (18.89 g, 26.28 mmol) was dissolved in dioxane(100 mL) to give a clear yellow solution at 0° C. 4N HCl (in dioxane, 35mL, 140 mmol) was added slowly with vigorous stirring. A yellow lump wasformed; the reaction flask was removed from the ice bath; then it wassonicated to break the lump then continued stirring at room temperature.A white solid was formed and collected to give the title compound (16.18g, 87% yield). LCMS m/z=619.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.57-1.74 (m, 2H), 1.74-1.86 (m, 3H), 2.16 (dd, J=13.39, 8.08 Hz, 1H),2.68-2.82 (m, 2H), 2.90-3.01 (m, 1H), 3.04-3.15 (m, 1H), 3.3-3.45 (m,2H), 3.72-3.80 (m, 1H), 3.82-3.93 (m, 2H), 4.04 (d, J=4.80 Hz, 2H),4.14-4.22 (m, 1H), 4.25 (s, 2H), 4.71 (bs, 2H), 7.26-7.33 (m, 2H), 7.39(t, J=1.77 Hz, 1H), 7.46 (d, J=8.08 Hz, 1H), 7.55 (t, J=7.96 Hz, 1H),7.60 (bs, 1H), 7.81 (td, J=7.58, 1.01 Hz, 1H), 8.01 (ddd, J=8.46, 6.95,1.52 Hz, 1H), 8.18 (d, J=8.59 Hz, 1H), 8.29 (d, J=7.58 Hz, 1H), 8.94 (d,J=1.77 Hz, 1H), 9.00 (bs, 1H), 9.11-9.21 (m, 2H). ¹³C NMR (400 MHz,CD₃OD) δ ppm 35.09, 37.00, 41.12, 44.33, 44.76, 50.34, 59.77, 62.50,66.61, 68.35, 71.57, 80.99, 115.36, 122.02, 122.29, 128.33, 129.58,130.06, 130.84, 131.61, 131.82, 134.46, 139.42, 141.86, 148.02, 149.86,160.26, 166.00.

Example 1.41 Preparation of(S)-1-((S)-8-(4′-(Aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 163). (Method F) Step A: Preparation of (S)-Benzyl3-(((S)-2-Hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol (380mg, 1.34 mmol) and (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.70 g, 2.41 mmol)were dissolved in EtOH (10 mL). The reaction was heated at 80° C.overnight. After cooling down to room temperature, the mixture wasconcentrated to give the title compound which was used directly in thenext step without further purification. LCMS m/z=575.6 [M+H]⁺.

Step B: Preparation of (S)-Benzyl3-((tert-Butoxycarbonyl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of (S)-benzyl3-(((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylatein CH₂Cl₂ (20 mL) were added DIEA (1.397 mL, 8.019 mmol) and (BOC)₂O(1.167 g, 5.346 mmol) at room temperature. Upon completion of thereaction monitored by TLC, the reaction was quenched with water. Thewater layer was extracted with CH₂Cl₂ (3×). The organic layers werecombined and washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (720 mg, 72.1% yield). LCMSm/z=675.2 [M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 1.04-1.08 (m, 2H),1.44-1.47 (m, 1H), 1.49 (s, 9H), 1.61-1.64 (m, 2H), 1.65-1.73 (m, 4H),1.77-1.84 (m, 1H), 2.08 (dd, J=8.85, 12.87 Hz, 1H), 3.30-3.40 (m, 2H),3.44-3.51 (t, J=4.20 Hz, 1H), 3.66 (s, 2H), 3.68-3.75 (m, 2H), 3.81 (dd,J=5.63, 9.65 Hz, 1H), 3.91-4.06 (m, 3H), 4.09-4.15 (m, 1H), 4.62 (t,J=6.98 Hz, 1H), 5.12 (s, 2H), 7.18-7.21 (m, 1H), 7.28-7.36 (m, 5H),7.41-7.42 (m, 1H), 7.46-7.52 (m, 2H).

Step C: Preparation of tert-Butyl((S)-2-Hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

Palladium/C (0.142 g, 1.336 mmol) was taken in to 50 mL round bottomflask with a septa and the vessel was evacuated and backfilled withargon. To that was added MeOH (20 mL) followed by (S)-benzyl3-((tert-butoxycarbonyl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (720 mg, 0.963mmol) in MeOH (5 mL). The reaction was stirred at room temperature for 2min, flushed with hydrogen and stirred at room temperature underhydrogen balloon for 5 h. The mixture was filtered through a pad ofcelite and washed with MeOH. The filtrate was concentrated to give thetitle compound (620 mg, 85.1% yield) as a white solid and used in thenext step without further purification. LCMS m/z=541.4 [M+H]⁺; ¹H NMR(400 M Hz, CD₃OD) δ ppm 1.07-1.11 (m, 2H), 1.47 (s, 9H), 1.47-1.52 (m,2H), 1.53-1.64 (m, 1H), 1.65-1.75 (m, 1H), 1.75-1.85 (m, 2H), 2.06-2.15(m, 2H), 2.80-2.91 (m, 2H), 2.95-3.08 (m, 2H), 3.25-3.36 (m, 1H), 3.57(dd, J=5.22, 15.09 Hz, 1H), 3.73 (s, 2H), 3.83 (dd, J=7.55, 9.29 Hz,1H), 3.94-4.05 (m, 2H), 4.05-4.11 (m, 1H), 4.14-4.20 (m, 1H), 4.52(quin, J=7.58 Hz, 1H), 7.29 (ddd, J=7.89, 2.59, 1.39 Hz, 1H), 7.45-7.56(m, 3H).

Step D: Preparation of tert-Butyl((S)-8-((5-Bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (380 mg,0.703 mmol) in CH₂Cl₂ (3.0 mL) was added DIEA (0.122 mL, 0.703 mmol)followed by addition of 5-bromo-2-ethoxybenzene-1-sulfonyl chloride(0.211 g, 0.703 mmol) at 0° C. The reaction was stirred at roomtemperature overnight. The mixture was concentrated and the residue waspurified by silica gel column chromatography to give the title compound(0.521 g, 86% yield) as a white solid. LCMS m/z=803.4 [M+H]⁺; ¹H NMR(400 M Hz, CDCl₃) δ ppm 1.05-1.08 (m, 2H), 1.45 (t, J=7.00 Hz, 3H), 1.49(s, 9H), 1.58-1.65 (m, 3H), 1.71-1.86 (m, 5H), 2.07 (dd, J=8.62, 12.93Hz, 1H), 3.04-3.14 (m, 2H), 3.46 (d, J=3.72 Hz, 2H), 3.53-3.58 (m, 2H),3.66 (s, 2H), 3.77 (dd, J=6.03, 9.48 Hz, 1H), 3.91 (dd, J=6.90, 9.48 Hz,1H), 3.96-4.04 (m, 2H), 4.09-4.15 (m, 3H), 4.55-4.62 (m, 1H), 6.86 (d,J=8.84 Hz, 1H), 7.18 (dt, J=2.31, 7.17 Hz, 1H), 7.40-7.41 (m, 1H),7.46-7.52 (m, 2H), 7.56 (dd, J=2.54, 8.80 Hz, 1H), 8.00 (d, J=2.52 Hz,1H).

Step E: Preparation of tert-Butyl((S)-8-((4′-(((tert-Butoxycarbonyl)amino)methyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl((S)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (0.521 g, 0.604 mmol) in EtOH/H₂O (4.5 mL, 2:1 ratio)were added potassium carbonate (97.14 mg, 0.703 mmol), Pd(dppf)₂ complexwith DCM (0.578 g, 0.703 mmol) and(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (0.176 g,0.703 mmol). The reaction was heated to 80° C. for 1 h. After coolingdown to room temperature, the reaction was diluted with EtOAc and washedwith water (3×) and brine then dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (440 mg, 61.5% yield) as awhite solid. LCMS m/z=930.6 [M+H]⁺.

Step F: Preparation of(S)-1-((S)-8-(4′-(Aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 163)

tert-Butyl((S)-8-((4′-(((tert-butoxycarbonyflamino)methyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (380 mg, 0.409 mmol) was dissolved inMeOH (1.0 mL) followed by addition of HCl (4N in dioxane, 1.5 mL, 6.128mmol) at room temperature. The reaction was stirred at room temperatureuntil the Boc-groups were cleaved (˜30 min). The mixture wasconcentrated and the residue was purified by prep-HPLC. Combinedfractions were concentrated and the residue was dissolved in water andneutralized with saturated aqueous NaHCO₃ (pH˜8). The aqueous layer wasextracted with 5% of MeOH/CH₂Cl₂ (3×). The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated. The residue wasdissolved in MeOH (1.0 mL) and added HCl (4N in dioxane, 1.532 mL, 6.128mmol). The solution was stood for 1 hour, concentrated then lyophilizedto give the title compound (263 mg, 80.2% yield) as a white solid. LCMSm/z=730.6 [M+H]⁺; ¹H NMR (400 M Hz, CD₃OD) δ ppm 1.07-1.10 (m, 2H), 1.48(t, J=7.00 Hz, 3H), 1.49-1.51 (m, 2H), 1.61-1.68 (m, 1H), 1.79-1.92 (m,4H), 2.36 (dd, J=8.09, 13.75 Hz, 1H), 3.08-3.21 (m, 3H), 3.32-3.36 (m,1H), 3.53-3.61 (m, 2H), 3.72 (s, 2H), 3.94 (dd, J=4.05, 9.71 Hz, 1H),4.01-4.08 (m, 1H), 4.08-4.14 (m, 3H), 4.16 (s, 2H), 4.26 (q, J=7.00 Hz,2H), 4.24-4.31 (m, 1H), 7.30 (d, J=8.72 Hz, 1H), 7.28-7.32 (m, 1H),7.47-7.52 (m, 3H), 7.55 (d, J=7.20 Hz, 2H), 7.69 (d, J=8.24 Hz, 2H),7.87 (dd, J=2.32, 8.71 Hz, 1H), 8.08 (d, J=2.36 Hz, 1H).

Example 1.42 Preparation of3-((R)-3-((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethyl-8-fluoroquinolin-4(1H)-one(Compound 333). (Method G) Step A: Preparation of tert-Butyl((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((8-fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (50 mg, 97.92 μmol) inCH₂Cl₂ (3.26 mL) under nitrogen were added DIEA (34.11 μL, 0.20 mmol)and 8-fluoro-4-hydroxyquinoline-3-sulfonyl chloride (28.18 mg, 0.11mmol). The reaction was stirred at room temperature until completion. Itwas then concentrated and purified by silica gel column chromatographyto give the title compound (76 mg, 95% yield) as a white solid. LCMSm/z=736.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.01-1.09 (m, 2H),1.18-1.23 (m, 2H), 1.32-1.36 (m, 1H), 1.45 (s, 9H), 1.57-1.65 (m, 1H),1.69-1.76 (m, 1H), 1.79 (t, J=5.94 Hz, 2H), 1.86 (dd, J=12.63, 8.08 Hz,1H), 2.07 (dd, J=12.63, 8.59 Hz, 1H), 2.66 (tt, J=7.83, 4.80 Hz, 1H),3.21-3.28 (m, 3H), 3.42-3.56 (m, 3H), 3.85-3.92 (m, 1H), 3.94-4.08 (m,3H), 4.11-4.19 (m, 1H), 4.52 (dd, J=13.89, 7.07 Hz, 1H), 7.27 (ddd,J=8.15, 2.59, 1.14 Hz, 1H), 7.42 (t, J=2.27 Hz, 1H), 7.43-7.53 (m, 3H),7.60 (ddd, J=10.80, 7.89, 1.26 Hz, 1H), 8.08 (d, J=8.34 Hz, 1H), 8.47(s, 1H).

Step B: Preparation of tert-Butyl((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((8-fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(76 mg, 0.10 mmol) in DMF (1.5 mL) under nitrogen was added DIEA (44.98μL, 0.258 mmol). The reaction was stirred at room temperature for 30min. Then bromoethane (43.3 μL, 0.77 mmol) was added. The reaction washeated under microwave irradiation at 110° C. for 4 h. The mixture waspurified by semi-prep HPLC to give the title compound (44 mg, 56% yield)as a white solid. LCMS m/z=764.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm1.01-1.08 (m, 2H), 1.17-1.23 (m, 2H), 1.45 (s, 9H), 1.52 (t, J=6.57 Hz,3H), 1.61 (ddd, J=13.39, 9.73, 3.92 Hz, 1H), 1.73 (ddd, J=13.52, 4.04,3.92 Hz, 1H), 1.79 (t, J=5.81 Hz, 2H), 1.86 (dd, J=12.76, 8.21 Hz, 1H),2.07 (dd, J=12.63, 8.59 Hz, 1H), 2.66 (tt, J=7.86, 4.77 Hz, 1H),3.20-3.30 (m, 3H), 3.41-3.57 (m, 3H), 3.83-3.91 (m, 1H), 3.94-4.08 (m,3H), 4.11-4.21 (m, 1H), 4.45-4.61 (m, 3H), 7.27 (ddd, J=8.08, 2.53, 1.01Hz, 1H), 7.42 (t, J=2.53 Hz, 1H), 7.43-7.47 (m, 1H), 7.49-7.55 (m, 2H),7.65 (ddd, J=14.91, 8.08, 1.52 Hz, 1H), 8.22 (dd, J=8.08, 1.01 Hz, 1H),8.56 (s, 1H).

Step C: Preparation of3-((R)-3-((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethyl-8-fluoroquinolin-4(1H)-one(Compound 333)

To a solution of tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(33 mg, 44.85 μmol) in THF (2 mL) was added HCl (2N in dioxane, 1 mL,2.0 mmol). The reaction was stirred at room temperature overnight. DCM(2 mL) was added to improve solubility and more of 2N HCl (in dioxane,0.5 mL) was added. After the reaction was completed, the mixture wasconcentrated and the residue was purified by prep-HPLC to give the titlecompound (26.3 mg, 87% yield) which was then converted to its HCl salt.LCMS m/z=664.6 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.02-1.10 (m, 2H),1.19-1.25 (m, 2H), 1.52 (t, J=6.57 Hz, 3H), 1.59-1.70 (m, 1H), 1.77-1.91(m, 4H), 2.35 (dd, J=13.64, 8.08 Hz, 1H), 2.67 (tt, J=7.96, 4.80 Hz,1H), 3.17-3.30 (m, 4H), 3.52-3.65 (m, 2H), 3.90-3.97 (m, 1H), 3.98-4.06(m, 1H), 4.06-4.15 (m, 3H), 4.21-4.30 (m, 1H), 4.55 (qd, J=7.07, 3.03Hz, 2H), 7.30 (ddd, J=7.89, 2.59, 1.39 Hz, 1H), 7.45 (t, J=2.27 Hz, 1H),7.49-7.59 (m, 3H), 7.67 (ddd, J=14.91, 8.08, 1.52 Hz, 1H), 8.22 (dd,J=8.46, 1.14 Hz, 1H), 8.58 (s, 1H). ¹³C NMR (400 MHz, CD₃OD) δ ppm 6.42,33.52, 35.72, 37.66, 41.14, 44.25, 44.68, 50.39, 59.86, 66.71, 68.37,71.62, 81.65, 114.53, 119.17, 119.33, 120.17, 121.10, 121.38, 122.44,122.48, 126.61, 126.68, 130.19, 130.57, 130.71, 132.02, 143.59, 145.09,152.63, 155.12, 160.48, 174.52, 174.55.

Example 1.43 Preparation of(S)-1-(3-(1,1-Difluoro-2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 130) Step A: Preparation of tert-Butyl((S)-3-(3-((1,1-Difluoro-2-hydroxyethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

(S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol (20mg, 67.96 μmol) and(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (37.78mg, 0.109 mmol) were dissolved in EtOH (0.5 mL). The reaction was heatedat 75° C. overnight. The mixture was concentrated and the residue waspurified by flash chromatography to give the title compound as a whitesolid.

Step B: Preparation of(S)-1-(3-(1,1-Difluoro-2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 130)

tert-Butyl((S)-3-(3-((1,1-difluoro-2-hydroxyethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamatewas dissolved in HCl (4N in Dioxane, 0.34 mL, 1.36 mmol) and stood for 2h. The mixture was concentrated to give the title compound (25.5 mg,50.5% yield) as a white solid. LCMS m/z=642.4 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.68-1.75 (m, 1H), 1.83-1.99 (m, 4H), 2.34 (dd, J=7.24,13.45 Hz, 1H), 2.89-3.00 (m, 2H), 3.13-3.18 (m, 1H), 3.25-3.33 (m, 1H),3.57-3.60 (m, 2H), 3.61-3.68 (m, 5H), 3.72-3.75 (m, 2H), 3.86-3.91 (m,1H), 3.99-4.05 (m, 2H), 4.09-4.12 (m, 1H), 4.14 (t, J=13.97 Hz, 2H),4.24-4.29 (m, 1H), 7.42-7.45 (m, 1H), 7.51 (bs, 1H), 7.59 (d, J=7.76 Hz,1H), 7.63 (t, J=7.76 Hz, 1H), 7.94 (t, J=7.50 Hz, 1H), 8.16 (t, J=7.54Hz, 1H), 8.27 (d, J=8.52 Hz, 1H), 8.35 (d, J=8.20 Hz, 1H), 9.21 (bs,1H), 9.36 (bs, 1H).

Example 1.44 Preparation of(S)-1-(3-(Methylsulfonyl)phenoxy)-3-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 3)

(S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (8 mg, 35.05 μmol) and(R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine(24.28 mg, 70.09 μmol) were dissolved in EtOH (1.5 mL). The reaction washeated at 60° C. overnight. After the reaction was completed and cooleddown to room temperature, it was concentrated and purified by massdirect prep-HPLC to give the title compound (15.1 mg, 62% yield). LCMSm/z=575.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.60-1.71 (m, 1H),1.76-1.95 (m, 4H), 2.29 (dd, J=13.77, 8.21 Hz, 1H), 2.73-2.91 (m, 2H),3.10 (s, 3H), 3.11-3.16 (m, 1H), 3.25 (dd, J=12.88, 3.03 Hz, 1H),3.43-3.55 (m, 2H), 3.80-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4.13 (m,2H), 4.17-4.27 (m, 1H), 7.25-7.33 (m, 1H), 7.49 (d, J=1.52 Hz, 1H), 7.55(d, J=5.56 Hz, 2H), 7.68 (qd, J=8.25, 8.08 Hz, 2H), 7.77 (dd, J=8.72,1.89 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.06-8.12 (m, 2H), 8.38 (d,J=1.26 Hz, 1H).

Example 1.45 Preparation of(S)-1-(3-(Methylsulfonyl)phenoxy)-3-((S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 4)

(S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (50 mg, 0.22 mmol) and(S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-aminehydrochloride (0.17 g, 0.44 mmol) were dissolved in EtOH (3 mL) followedby addition of DIEA (83.94 μL, 0.482 mmol). The reaction was heated at60° C. overnight. After the reaction was completed, it was cooled downto room temperature, concentrated, and then purified by mass directprep-HPLC. The TFA salt obtained was lyophilized and re-dissolved inMeOH. The solution was passed through a SCX cartridge and washed with 2NNH₃ in MeOH. The filtrate was added HCl (4N in dioxane, 400 μL) andconcentrated to give the title compound (27 mg, 20% yield) as a whitesolid. LCMS m/z=575.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61-1.71(m, 1H), 1.76-1.96 (m, 4H), 2.29 (dd, J=13.64, 8.34 Hz, 1H), 2.73-2.89(m, 2H), 3.05-3.15 (m, 4H), 3.27 (dd, J=12.88, 3.03 Hz, 1H), 3.44-3.56(m, 2H), 3.78-3.86 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4.13 (m, 2H),4.18-4.26 (m, 1H), 7.25-7.32 (m, 1H), 7.49 (d, J=1.52 Hz, 1H), 7.54-7.58(m, 2H), 7.63-7.74 (m, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d,J=8.08 Hz, 1H), 8.05-8.12 (m, 2H), 8.38 (d, J=1.52 Hz, 1H).

Example 1.46 Preparation of(2S)-1-(8-(4′-((Methylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol(Compound 78). (Method H) Step A: Preparation of tert-Butyl((S)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

From (S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane and benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, the title compoundwas prepared using a similar method to the one described in Method A,Step A, B, and C.

Step B: Preparation of tert-Butyl(8-((3-Bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(243 mg, 0.50 mmol) in THF (7 mL) under nitrogen was added DIEA (0.18mL, 1.00 mmol) and 3-bromobenzene-1-sulfonyl chloride (0.17 g, 0.65mmol). The reaction was stirred at room temperature overnight. After thereaction was completed, the mixture was concentrated. The residue waspurified by silica gel column chromatography to give the title compound(313 mg, 89% yield) as a white foam. LCMS m/z=705.3 [M+H]⁺; ¹H NMR (400MHz, CD₃OD) δ ppm 1.44 (s, 9H), 1.57-1.67 (m, 1H), 1.71-1.79 (m, 1H),1.79-1.87 (m, 2H), 1.98-2.05 (m, 1H), 2.77 (ddd, J=15.03, 11.87, 11.75Hz, 2H), 3.11 (s, 3H), 3.21-3.27 (m, 1H), 3.34-3.41 (m, 3H), 3.53 (dd,J=14.65, 4.55 Hz, 1H), 3.80-3.90 (m, 1H), 3.93-4.10 (m, 3H), 4.11-4.18(m, 1H), 4.43-4.51 (m, 1H), 7.28 (dt, J=5.87, 3.00 Hz, 1H), 7.48 (d,J=1.52 Hz, 1H), 7.51-7.58 (m, 3H), 7.75 (d, J=7.83 Hz, 1H), 7.84 (d,J=8.08 Hz, 1H), 7.90 (t, J=1.77 Hz, 1H).

Step C: Preparation of tert-Butyl((S)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a 20 mL microwave vial containing a magnetic stir bar were addedPd(dppf)₂, DCM (0.54 g, 0.65 mmol) and (4-(hydroxymethyl)phenyl)boronicacid (59.34 mg, 0.39 mmol). A solution of tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate(229 mg, 0.33 mmol) and a solution of sodium carbonate (0.358 mL, 0.716mmol) were then added to the reaction vial. The resulting mixture washeated at 90° C. overnight. After the reaction was completed, it wasdiluted in EtOAc then washed with water and brine. The organic layer wasdried over Mg₂SO₄, filtered and concentrated. The residue was purifiedby silica gel column chromatography to give the title compound (209 mg,87% yield). LCMS m/z=731.5 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.43(s, 9H), 1.56-1.69 (m, 1H), 1.70-1.79 (m, 1H), 1.79-1.89 (m, 2H),1.95-2.10 (m, 2H), 2.74-2.85 (m, 2H), 3.09 (s, 3H), 3.16-3.27 (m, 1H),3.35-3.44 (m, 2H), 3.46-3.55 (m, 1H), 3.70-4.07 (m, 4H), 4.09-4.18 (m,1H), 4.42-4.51 (m, 1H), 4.67 (s, 2H), 7.21-7.31 (m, 1H), 7.45-7.54 (m,5H), 7.63-7.72 (m, 3H), 7.72-7.77 (m, 1H), 7.92-8.00 (m, 3H).

Step D: Preparation of tert-Butyl((S)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4′-((methylamino)methyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(10 mg, 13.68 μmol) in dioxane (1 mL) was added methanesulfonyl chloride(9.53 μL, 123.15 μmol). The reaction was stirred at room temperatureovernight. Next day, methanamine (637.4 μg, 20.52 μmol) was added andthe reaction was stirred overnight. After the reaction was completed, itwas quenched with water and purified via mass directed prep-HPLC. Theappropriated fractions were lyophilized to give the title compound as awhite solid. LCMS m/z=744.4 [M+H]⁺.

Step E: Preparation of(2S)-1-(8-(4′-((Methylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol(Compound 78)

The TFA salt of tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4′-((methylamino)methyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamatewas dissolved in ACN (2 mL) and added HCl (4N in dioxane, 51.31 μL, 0.21mmol). The reaction was stirred at room temperature for 3 h. The mixturewas then concentrated and purified by prep-HPLC to give the titlecompound (4.8 mg, 46% yield). LCMS m/z=644.4 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.68 (m, 1H), 1.79-1.97 (m, 4H), 2.31 (ddd, J=13.77, 8.21,2.02 Hz, 1H), 2.69-2.85 (m, 5H), 3.11 (s, 3H), 3.12-3.19 (m, 1H),3.25-3.29 (m, 1H), 3.42-3.55 (m, 2H), 3.83-3.93 (m, 1H), 3.95-4.07 (m,2H), 4.07-4.15 (m, 2H), 4.21-4.30 (m, 3H) 7.26-7.33 (m, 1H), 7.49 (t,J=1.25 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H), 7.62 (d, J=8.34 Hz, 2H), 7.74(t, J=8.34 Hz, 1H), 7.76-7.83 (m, 3H), 7.94-8.01 (m, 2H).

Example 1.47 Preparation of(S)-1-((R)-8-(1H-Pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol(Compound 320) Step A: Preparation of tert-Butyl((R)-8-((1H-Pyrrolo[3,2-b]pyridin-6-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(30 mg, 61.91 μmol) in CH₂Cl₂ (5 mL) was added DIEA (12.94 μL, 74.29μmol) and 1H-pyrrolo[3,2-b]pyridine-6-sulfonyl chloride (16.09 mg, 74.29μmol). The reaction was stirred at room temperature under nitrogen.After the reaction was completed, the mixture was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (14 mg, 34% yield). LCMS m/z=665.4 [M+H]⁺.

Step B: Preparation of(S)-1-((R)-8-(1H-Pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol(Compound 320)

tert-Butyl((R)-8-((1H-pyrrolo[3,2-b]pyridin-6-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate(14 mg, 21.1 μmol) was dissolved in DCM (3 mL) following by addition ofHCl (4N in dioxane, 0.2 mL). The reaction was stirred at roomtemperature until completion. The mixture was concentrated to give awhite solid which was then triturated with MeCN to give the titlecompound (11.2 mg, 28% yield) as a solid. LCMS m/z=565.4 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.56-1.87 (m, 5H), 2.15 (dd, J=13.64, 8.08 Hz,1H), 2.57-2.73 (m, 2H), 2.89-3.01 (m, 1H), 3.07-3.15 (m, 1H), 3.21 (s,3H), 3.25-3.37 (m, 2H), 3.64-3.98 (m, 4H), 4.06 (d, J=5.05 Hz, 2H),4.13-4.20 (m, 1H), 6.78 (bs, 1H), 7.29 (ddd, J=8.08, 2.53, 1.01 Hz, 1H),7.43 (d, J=1.77 Hz, 1H), 7.48-7.54 (m, 1H), 7.58 (t, J=7.96 Hz, 1H),8.06 (d, J=2.27 Hz, 1H), 8.20 (bs, 1H), 8.68 (s, 1H), 8.95 (bs, 1H),9.08 (bs, 1H), 12.05 (bs, 1H).

Example 1.48 Preparation of(S)-1-((R)-8-(1H-Pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(isopropylsulfonyl)phenoxy)propan-2-ol(Compound 321). (Method E3) Step A: Preparation of tert-butyl((R)-8-((1H-Pyrrolo[3,2-b]pyridin-6-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate

From (S)-2-((3-(isopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate and tert-butyl6-(chlorosulfonyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate, the titlecompound was prepared using a similar method to the one described inMethod E, Step A, B and C. LCMS m/z=793.6 [M+H]⁺.

Step B: Preparation of(S)-1-((R)-8-(1H-Pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(isopropylsulfonyl)phenoxy)propan-2-ol(Compound 321)

From tert-butyl((R)-8-((1H-pyrrolo[3,2-b]pyridin-6-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate,the title compound was prepared using a similar method to the onedescribed in Method G, Step C. LCMS m/z=593.4 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.24 (d, J=6.82 Hz, 6H), 1.65-1.78 (m, 1H), 1.83-1.99 (m,4H), 2.36 (dd, J=13.64, 7.83 Hz, 1H), 2.83-2.99 (m, 2H), 3.16 (dd,J=12.63, 9.85 Hz, 1H), 3.27 (d, J=3.03 Hz, 1H), 3.32-3.37 (m, 1H),3.55-3.64 (m, 2H), 3.64-3.76 (m, 1H), 3.86-3.95 (m, 1H), 3.99-4.07 (m,2H), 4.07-4.15 (m, 2H), 4.23-4.32 (m, 1H), 7.04 (d, J=3.23 Hz, 1H), 7.33(dd, J=8.34, 1.77 Hz, 1H), 7.42 (t, J=1.52 Hz, 1H), 7.48 (d, J=7.83 Hz,1H), 7.57 (t, J=7.96 Hz, 1H), 8.42 (d, J=3.28 Hz, 1H), 8.86 (s, 1H),9.05 (d, J=1.26 Hz, 1H).

Example 1.49 Preparation of1-Ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 322) Step A: Preparation of tert-Butyl((R)-8-((8-Fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

From tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(40.0 mg, 82.54 μmol) and 8-fluoro-4-hydroxyquinoline-3-sulfonylchloride, the title compound was prepared using a similar method to theone described in Method G, Step A. LCMS m/z=710.6 [M+H]⁺; ¹H NMR (400MHz, CD₃OD) δ ppm 1.45 (s, 9H), 1.61 (ddd, J=13.39, 5.18, 4.93 Hz, 1H),1.69-1.77 (m, 1H), 1.80 (t, J=8 Hz, 2H), 1.86 (dd, J=12.63, 8.08 Hz,1H), 2.08 (dd, J=12.76, 8.46 Hz, 1H), 3.09 (s, 3H), 3.22-3.29 (m, 3H),3.42-3.56 (m, 4H), 3.85-3.92 (m, 1H), 3.96-4.08 (m, 3H), 4.12-4.19 (m,1H), 4.47-4.57 (m, 1H), 7.28 (dt, J=7.39, 2.24 Hz, 1H), 7.43-7.55 (m,4H), 7.61 (ddd, J=10.80, 8.02, 1.14 Hz, 1H), 8.08 (d, J=8.34 Hz, 1H),8.47 (s, 1H).

Step B: Preparation of1-Ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 322)

To a solution of tert-butyl((R)-8-((8-fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate(48 mg, 67.62 μmol) in DMF (2 mL) was added iodoethane (81.13 μL, 1.01mmol) and DIEA (0.18 mL, 1.01 mmol). The reaction was heated at 120° C.for 2.5 h. After the reaction was completed, it was diluted in EtOActhen washed with water (2×) and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel column chromatography to give tert-butyl((R)-8-((1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate.LCMS m/z=738.6 [M+H]⁺.

tert-Butyl((R)-8-((1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamatefrom the previous step was dissolved in EtOAc (2 mL) followed byaddition of HCl (4N in dioxane, 0.4 mL). The reaction was stirred atroom temperature until completion. The mixture was concentrated and theresidue was purified by HPLC to give the FTA salt of the title compound.The TFA salt was lyophilized then neutralized. The obtained material wasdissolved in EtOAc (2 mL) and treated with HCl (4N in dioxane, 0.1 mL).The mixture was concentrated to give HCl salt of the title compound(36.2 mg, 75% yield) as a white solid. LCMS m/z=638.6 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.40 (t, J=6.69 Hz, 3H), 1.52-1.61 (m, 1H),1.62-1.71 (m, 1H), 1.72-1.83 (m, 3H), 2.20 (dd, J=13.26, 7.96 Hz, 1H),2.94-3.05 (m, 1H), 3.06-3.20 (m, 3H), 3.22 (s, 3H), 3.33-3.43 (m, 2H),3.77-3.86 (m, 1H), 3.87-3.99 (m, 2H), 4.07 (d, J=5.05 Hz, 2H), 4.13-4.22(m, 1H), 4.44-4.54 (m, 1H), 5.91 (d, J=4.80 Hz, 1H), 7.30 (dd, J=8.08,1.77 Hz, 1H), 7.44 (t, J=2.02 Hz, 1H), 7.49-7.56 (m, 2H), 7.59 (t,J=7.96 Hz, 1H), 7.76 (ddd, J=15.03, 7.96, 1.52 Hz, 1H), 8.11 (d, J=7.83Hz, 1H), 8.56 (s, 1H), 8.91 (bs, 1H), 8.98 (bs, 1H).

Example 1.50 Preparation of3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 326) as the HCl Salt Step A: Preparation of tert-Butyl((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

From tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamateand 4-hydroxyquinoline-3-sulfonyl chloride, the title compound wasprepared using a similar method to the one described in Method G, StepA. LCMS m/z=718.6 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.00-1.09 (m,2H), 1.18-1.23 (m, 2H), 1.45 (s, 9H), 1.56-1.66 (m, 1H), 1.68-1.76 (m,1H), 1.80 (t, J=6.82 Hz, 2H), 1.86 (dd, J=12.88, 8.34 Hz, 1H), 2.07 (dd,J=12.76, 8.46 Hz, 1H), 2.62-2.71 (m, 1H), 3.20-3.28 (m, 3H), 3.38-3.57(m, 4H), 3.84-3.92 (m, 1H), 3.95-4.06 (m, 3H), 4.11-4.19 (m, 1H),4.44-4.56 (m, 1H), 7.26 (dt, J=8.08, 1.26 Hz, 1H), 7.39-7.46 (m, 2H),7.47-7.54 (m, 2H), 7.62 (d, J=7.83 Hz, 1H), 7.76-7.82 (m, 1H), 8.29 (dd,J=8.08, 1.01 Hz, 1H), 8.51 (s, 1H).

Step B: Preparation of3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 326) as the HCl Salt

To a solution of tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(17 mg, 23.68 μmol) in THF/DCM (1:1 ratio, 4 mL) was added HCl (4N indioxane, 1 mL, 1.0 mmol). The reaction was stirred at room temperatureuntil completion. The mixture was concentrated and the residue waspurified by prep-HPLC to give the TFA salt of the title compound. TheTFA salt was lyophilized and converted to the HCl salt of the titlecompound (12.1 mg, 78.1% yield). LCMS m/z=618.4 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.02-1.10 (m, 2H), 1.19-1.25 (m, 2H), 1.31-1.34 (m, 1H),1.56-1.72 (m, 1H), 1.77-1.91 (m, 4H), 2.33-2.39 (m, 1H), 2.62-2.71 (m,1H), 3.14-3.29 (m, 3H), 3.50-3.63 (m, 2H), 3.90-3.97 (m, 1H), 3.98-4.06(m, 1H), 4.07-4.15 (m, 3H), 4.22-4.29 (m, 1H), 7.30 (ddd, J=7.89, 2.59,1.39 Hz, 1H), 7.45 (t, J=2.27 Hz, 1H), 7.49-7.59 (m, 3H), 7.63 (d,J=8.08 Hz, 1H), 7.80 (ddd, J=8.40, 7.01, 1.52 Hz, 1H), 8.29 (dd, J=8.08,1.01 Hz, 1H), 8.53 (s, 1H).

Example 1.51 Preparation of3-((R)-3-((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-8-methylquinolin-4-ol.(Compound 327) Step A: Preparation of tert-Butyl((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((4-hydroxy-8-methylquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

From tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamateand 4-hydroxy-8-methylquinoline-3-sulfonyl chloride, the title compoundwas prepared using a similar method to the one described in Method G,Step A. LCMS m/z=732.6 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.01-1.10(m, 2H), 1.30-1.37 (m, 2H), 1.47 (s, 9H), 1.66 (dd, J=11.24, 4.17 Hz,1H), 1.75-1.92 (m, 5H), 2.04 (dd, J=13.01, 8.72 Hz, 1H), 2.47 (tt,J=7.93, 4.71 Hz, 1H), 2.63 (s, 3H), 2.65-2.78 (m, 2H), 3.36 (bs, 1H),3.43-3.55 (m, 3H), 3.73-3.86 (m, 2H), 3.92-4.03 (m, 2H), 4.09-4.18 (m,1H), 4.51-4.64 (m, 1H), 6.48 (d, J=7.33 Hz, 1H), 7.14 (dt, J=6.88, 2.49Hz, 1H), 7.38 (d, J=1.52 Hz, 1H), 7.46-7.51 (m, 2H), 7.82 (d, J=1.26 Hz,1H), 7.86 (d, J=7.58 Hz, 1H), 8.63 (d, J=1.77 Hz, 1H), 9.63 (bs, 1H).

Step B: Preparation of3-((R)-3-((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-8-methylquinolin-4-ol.(Compound 327)

From tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((4-hydroxy-8-methylquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,the title compound was prepared using a similar method to the onedescribed in Method G, Step C. LCMS m/z=632.6 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.02-1.10 (m, 2H), 1.18-1.25 (m, 2H), 1.64-1.75 (m, 1H),1.80-1.98 (m, 4H), 2.33 (dd, J=13.77, 7.96 Hz, 1H), 2.67 (tt, J=7.96,4.80 Hz, 1H), 2.71-2.87 (m, 5H), 3.15 (dd, J=12.76, 9.73 Hz, 1H),3.24-3.30 (m, 1H), 3.49-3.61 (m, 2H), 3.82-3.91 (m, 1H), 3.96-4.04 (m,2H), 4.06-4.14 (m, 2H), 4.21-4.29 (m, 1H), 6.99 (d, J=7.07 Hz, 1H), 7.29(ddd, J=8.02, 2.46, 1.39 Hz, 1H), 7.44 (d, J=2.27 Hz, 1H), 7.48-7.59 (m,2H), 8.09 (d, J=1.01 Hz, 1H), 8.55 (d, J=6.82 Hz, 1H), 8.61 (d, J=1.52Hz, 1H).

Example 1.52 Preparation of3-((R)-3-((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-7-fluoroquinolin-4-ol(Compound 329) Step A: Preparation of tert-Butyl((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((7-fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

From tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamateand 7-fluoro-4-hydroxyquinoline-3-sulfonyl chloride, the title compoundwas prepared using a similar method to the one described in Method G,Step A. LCMS m/z=736.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.00-1.09(m, 2H), 1.17-1.24 (m, 2H), 1.45 (s, 9H), 1.56-1.66 (m, 1H), 1.69-1.81(m, 3H), 1.86 (dd, J=12.76, 8.21 Hz, 1H), 2.07 (dd, J=12.88, 8.59 Hz,1H), 2.67 (tt, J=7.96, 4.80 Hz, 1H), 3.21-3.29 (m, 3H), 3.39-3.50 (m,2H), 3.53 (dd, J=14.53, 4.67 Hz, 1H), 3.85-3.91 (m, 1H), 3.95-4.08 (m,3H), 4.11-4.20 (m, 1H), 4.45-4.58 (m, 1H), 7.24-7.35 (m, 3H), 7.40-7.47(m, 2H), 7.51 (t, J=7.96 Hz, 1H), 8.33 (dd, J=9.09, 6.06 Hz, 1H), 8.51(s, 1H).

Step B: Preparation of3-((R)-3-((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-7-fluoroquinolin-4-ol(Compound 329)

From tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((7-fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,the title compound was prepared using a similar method to the onedescribed in Method E, Step D. LCMS m/z=636.6 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.03-1.11 (m, 2H), 1.18-1.26 (m, 2H), 1.59-1.71 (m, 1H),1.76-1.90 (m, 4H), 2.35 (dd, J=13.89, 8.34 Hz, 1H), 2.67 (tt, J=7.96,4.80 Hz, 1H), 3.16-3.30 (m, 3H), 3.51-3.62 (m, 2H), 3.64-3.70 (m, 1H),3.72-3.76 (m, 1H), 3.91-3.97 (m, 1H), 3.98-4.06 (m, 1H), 4.06-4.15 (m,3H), 4.26 (td, J=4.80, 3.03 Hz, 1H), 7.25-7.36 (m, 3H), 7.46 (t, J=2.27Hz, 1H), 7.50-7.59 (m, 2H), 8.33 (dd, J=9.09, 5.81 Hz, 1H), 8.53 (s,1H).

Example 1.53 Preparation of1-Ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 331) Step A: Preparation of tert-Butyl((R)-8-((8-Fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate

From (S)-2-((3-(isopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate and8-fluoro-4-hydroxyquinoline-3-sulfonyl chloride, the title compound wasprepared using a similar method to the one described in Method E, StepA, B, and C. LCMS m/z=738.6 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.23(d, J=6.82 Hz, 6H), 1.45 (s, 9H), 1.61 (ddd, J=13.64, 9.85, 4.04 Hz,1H), 1.73 (ddd, J=13.52, 4.04, 3.92 Hz, 1H), 1.79 (t, J=5.81 Hz, 2H),1.86 (dd, J=12.76, 8.21 Hz, 1H), 2.07 (dd, J=12.76, 8.46 Hz, 1H),3.20-3.29 (m, 4H), 3.42-3.57 (m, 3H), 3.85-3.91 (m, 1H), 3.95-4.02 (m,2H), 4.02-4.07 (m, 1H), 4.11-4.19 (m, 1H), 4.52 (dd, J=15.66, 8.34 Hz,1H), 7.29 (ddd, J=8.34, 2.53, 1.01 Hz, 1H), 7.39 (t, J=2.53 Hz, 1H),7.40-7.44 (m, 1H), 7.44-7.49 (m, 1H), 7.53 (t, J=7.96 Hz, 1H), 7.60(ddd, J=10.86, 8.08, 1.26 Hz, 1H), 8.08 (d, J=8.08 Hz, 1H), 8.48 (s,1H).

Step B: Preparation of tert-Butyl((R)-8-((1-Ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate

From tert-butyl((R)-8-((8-fluoro-4-hydroxyquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamateand ethyl iodide, the title compound was prepared using a similar methodto the one described in Method G, Step B. LCMS m/z=766.6 [M+H]⁺.

Step C: Preparation of1-Ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 331)

From of tert-butyl((R)-8-((1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate,the title compound was prepared using a similar method to the onedescribed in Method E, Step D. LCMS m/z=666.6 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.25 (d, J=7.07 Hz, 6H), 1.52 (t, J=6.57 Hz, 3H), 1.60-1.69(m, 1H), 1.77-1.90 (m, 4H), 2.35 (dd, J=13.77, 8.21 Hz, 1H), 3.16-3.29(m, 4H), 3.53-3.69 (m, 3H), 3.91-3.97 (m, 1H), 3.99-4.15 (m, 4H), 4.26(dddd, J=9.60, 4.99, 4.86, 3.28 Hz, 1H), 4.55 (qd, J=7.12, 2.91 Hz, 2H),7.33 (ddd, J=8.15, 2.59, 0.88 Hz, 1H), 7.43 (t, J=2.53 Hz, 1H),7.47-7.51 (m, 1H), 7.53 (dt, J=8.02, 3.95 Hz, 1H), 7.58 (t, J=7.96 Hz,1H), 7.67 (ddd, J=14.91, 7.83, 1.52 Hz, 1H), 8.22 (d, J=8.08 Hz, 1H),8.58 (s, 1H).

Example 1.54 Preparation of1-Ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 332) Step A: Preparation of tert-Butyl((S)-2-Hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

From (S)-2-((3-(isopropylsulfonyl)phenoxy)methyl)oxirane and (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, the title compoundwas prepared using a similar method to the one described in Method A,Step A, B and C.

Step B: Preparation of1-Ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 332)

From tert-butyl((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamateand 1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride, tert-butyl((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamatewas prepared using a similar method to the one described in Method A,Step F.

From tert-butyl((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propyl)carbamate,the title compound was prepared in a similar method described in MethodG, Step C. LCMS m/z=648.6 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.25 (d,J=6.82 Hz, 6H), 1.52 (t, J=7.20 Hz, 3H), 1.60-1.70 (m, 1H), 1.77-1.90(m, 4H), 2.35 (dd, J=13.77, 8.21 Hz, 1H), 3.14-3.30 (m, 4H), 3.52-3.64(m, 2H), 3.90-3.96 (m, 1H), 3.97-4.05 (m, 1H), 4.05-4.14 (m, 3H),4.19-4.30 (m, 1H), 4.48 (q, J=7.07 Hz, 2H), 7.33 (ddd, J=8.27, 2.59,1.01 Hz, 1H), 7.43 (t, J=2.27 Hz, 1H), 7.49 (dt, J=8.00, 1.26 Hz, 1H),7.54-7.61 (m, 2H), 7.85-7.92 (m, 2H), 8.38 (d, J=7.83 Hz, 1H), 8.68 (s,1H).

Example 1.55 Preparation of(S)-1-((R)-8-(4′-(Aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol(Compound 189) Step A: Preparation of tert-Butyl((R)-8-((3-Bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate

To a solution of tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(81 mg, 0.16 mmol) in CH₂Cl₂ (5 mL) was added DIEA (69.07 μL, 0.40 mmol)and 3-bromobenzene-1-sulfonyl chloride (48.64 mg, 0.19 mmol) undernitrogen. The reaction mixture was stirred at room temperatureovernight. After the reaction was completed, the mixture wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (88 mg, 76% yield) ascolorless oil. LCMS m/z=729.6 [M]+; ¹H NMR (400 MHz, CD₃OD) δ ppm1.03-1.09 (m, 2H), 1.19-1.26 (m, 2H), 1.44 (s, 9H), 1.57-1.68 (m, 1H),1.71-1.89 (m, 4H), 2.00-2.07 (m, 1H), 2.61-2.85 (m, 3H), 3.18-3.28 (m,1H), 3.33-3.40 (m, 2H), 3.53 (dd, J=14.65, 4.55 Hz, 1H), 3.79-3.88 (m,1H), 3.91-4.19 (m, 5H), 4.44-4.53 (m, 1H), 7.27 (ddd, J=7.89, 2.59, 1.14Hz, 1H), 7.43 (t, J=2.27 Hz, 1H), 7.47-7.57 (m, 3H), 7.75 (ddd, J=7.83,1.77, 1.01 Hz, 1H), 7.84 (ddd, J=7.89, 1.96, 1.01 Hz, 1H), 7.90 (t,J=1.77 Hz, 1H).

Step B: Preparation of(S)-1-((R)-8-(4′-(Aminomethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol(Compound 189)

A solution of tert-butyl((R)-8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate(32 mg, 43.85 μmol), Pd(dppf)₂, DCM (5.41 mg, 6.6 μmol), sodiumcarbonate (48.24 μL, 96.48 μmol) and(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (13.21 mg,52.62 μmol) in dioxane (4 mL) was degassed with N₂ for 10 min thenheated at 100° C. overnight. After the reaction was completed and cooleddown to room temperature, solid Na₂SO₄ was added. The mixture wasstirred for 2 h and filtered through a pad of Celite® and Na₂SO₄. Thefiltrate was washed with DCM/MeOH (5%) and concentrated. The residue waspurified by silica gel column chromatography to give tert-butyl((R)-8-((4′-(((tert-butoxycarbonyl)amino)methyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate.LCMS m/z=857.8 [M+H]⁺.

To a solution of tert-butyl((R)-8-((4′-(((tert-butoxycarbonyl)amino)methyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamatefrom the previous step in MeCN (4.0 mL) was added HCl (4N in dioxane,0.3 mL). The reaction was stirred at room temperature until completion.The mixture was concentrated. The residue was purified by prep-HPLC. Thecollected fractions was added HCl (4N in dioxane, 200 μL) andlyophilized to give the title compound (24 mg, 74% yield) as a solid.LCMS m/z=656.6 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD) δ ppm 1.03-1.10 (m, 2H),1.19-1.25 (m, 2H), 1.61-1.74 (m, 1H), 1.79-1.94 (m, 4H), 2.33 (dd,J=13.77, 8.21 Hz, 1H), 2.63-2.71 (m, 1H), 2.71-2.84 (m, 2H), 3.16 (dd,J=12.38, 9.35 Hz, 1H), 3.45-3.56 (m, 2H), 3.56-3.77 (m, 2H), 3.86-3.92(m, 1H), 3.96-4.04 (m, 2H), 4.10 (dd, J=5.18, 2.91 Hz, 2H), 4.20 (s,2H), 4.22-4.29 (m, 1H), 7.29 (ddd, J=7.89, 2.59, 1.39 Hz, 1H), 7.45 (t,J=2.27 Hz, 1H), 7.50-7.63 (m, 4H), 7.70-7.83 (m, 4H), 7.95-8.00 (m, 2H).

Example 1.56 Preparation of(S)-1-((S)-8-(4′-(Aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)propan-2-ol(Compound 209). (Method I) Step A: Preparation of (S)-Benzyl3-(((S)-3-(3-Bromo-2-fluorophenoxy)-2-hydroxypropyl)(tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

A solution of (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.65 g, 2.23 mmol)and (S)-2-((3-bromo-2-fluorophenoxy)methyl)oxirane (0.28 g, 1.12 mmol)in EtOH (15 mL) was heated at 70° C. overnight under nitrogen. After thereaction was completed, the mixture was concentrated to give (S)-benzyl3-(((S)-3-(3-bromo-2-fluorophenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(0.55 g, 92% yield) as a yellow oil without further purification. LCMSm/z=537.2 [M]⁺.

A solution of (S)-benzyl3-(((S)-3-(3-bromo-2-fluorophenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylatefrom the previous step (0.55 g, 1.02 mmol) in CH₂Cl₂ (15 mL) were added(BOC)₂O (0.49 g, 2.23 mmol) and DIEA (0.20 mL, 1.12 mmol). The reactionwas stirred at room temperature overnight under nitrogen. After thereaction was completed, the mixture was concentrated. The residue waspurified by silica gel column chromatography to give the title compound(565 mg, 79% yield) as a clear gum. LCMS m/z=637.4 [M]⁺; ¹H NMR (400MHz, CD₃OD) δ ppm 1.42-1.54 (m, 11H), 1.59-1.68 (m, 1H), 1.69-1.77 (m,2H), 2.02-2.14 (m, 2H), 3.40 (bs, 2H), 3.56 (dd, J=14.53, 4.67 Hz, 1H),3.59-3.70 (m, 2H), 3.83 (dd, J=8.84, 7.33 Hz, 1H), 3.93-4.11 (m, 3H),4.12-4.21 (m, 1H), 4.46-4.58 (m, 1H), 5.11 (s, 2H), 7.03 (td, J=8.21,1.64 Hz, 1H), 7.09 (td, J=7.45, 1.64 Hz, 1H), 7.16 (ddd, J=7.89, 6.00,1.52 Hz, 1H), 7.26-7.40 (m, 5H).

Step B: Preparation of (S)-Benzyl3-((tert-Butoxycarbonyl)((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyflamino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a 5 mL microwave vial were added (S)-benzyl3-(((S)-3-(3-bromo-2-fluorophenoxy)-2-hydroxypropyl)(tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(150 mg, 0.24 mmol), Sodium methansulfinate (108.06 mg, 0.71 mmol),Copper(I) trifluoromethanesulfonate-benzene complex (26.06 mg, 70.56μmol), and N₁,N₂-dimethylethane-1,2-diamine (12.45 mg, 141.22 μmol)under N₂ followed by DMSO (4 mL). The reaction was heated at 110° C. for4 h under microwave irradiation. The mixture was diluted in EtOAc andwashed with water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gel columnchromatography to give the title compound (96 mg, 64% yield) as acolorless oil. LCMS m/z=637.8 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.46(s, 9H), 1.47-1.55 (m, 1H), 1.61-1.70 (m, 1H), 1.70-1.78 (m, 2H),2.04-2.15 (m, 2H), 3.23 (s, 3H), 3.34-3.46 (m, 2H), 3.58 (dd, J=14.65,4.55 Hz, 1H), 3.61-3.71 (m, 2H), 3.84 (dd, J=8.84, 7.33 Hz, 1H), 3.97(dd, J=8.97, 7.71 Hz, 1H), 4.06-4.16 (m, 2H), 4.16-4.23 (m, 1H),4.51-4.58 (m, 1H), 5.11 (s, 2H), 7.27-7.38 (m, 6H), 7.43-7.53 (m, 2H).

Step C: Preparation of tert-Butyl((S)-3-(2-Fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of (S)-benzyl3-((tert-butoxycarbonyl)((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(96 mg, 0.15 mmol) in MeOH (10 mL) under N₂ was added Palladium/C (16.05mg, 15.08 μmol) followed by addition of H₂ balloon. The reaction wasstirred at room temperature overnight. After the reaction was completed,it was filtered through a pad of Celite®, washed with MeOH andconcentrated to give the title compound (76 mg, 100% yield) as a whitefoam which was used in the next step without further purification. LCMSm/z=503.4 [M+H]⁺.

Step D: Preparation of tert-Butyl((S)-8-((5-Bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate

To a solution of tert-butyl((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamateand DIEA (65.85 μL, 0.38 mmol) in CH₂Cl₂ (10 mL) was added5-bromo-2-ethoxybenzene-1-sulfonyl chloride (70.78 mg, 0.23 mmol) undernitrogen. The reaction was stirred at room temperature for 6 h. Themixture was concentrated. The residue was purified by silica gel columnchromatography to give the title compound (55 mg, 48% yield) as a whitefoam. LCMS m/z=767.4 [M+2H]⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.42-1.52(m, 12H), 1.60-1.89 (m, 6H), 2.04-2.12 (m, 1H), 3.03-3.16 (m, 2H), 3.21(s, 3H), 3.44-3.52 (m, 2H), 3.59 (dd, J=13.01, 4.42 Hz, 2H), 3.78 (dd,J=9.60, 6.57 Hz, 1H), 3.92 (dd, J=9.47, 7.45 Hz, 1H), 3.98-4.05 (m, 1H),4.05-4.19 (m, 4H), 4.48-4.67 (m, 1H), 6.87 (d, J=8.59 Hz, 1H), 7.21-7.32(m, 2H), 7.56 (dd, J=11.87, 9.35 Hz, 2H), 8.01 (d, J=2.53 Hz, 1H).

Step E: Preparation of(S)-1-((S)-8-(4′-(Aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)propan-2-ol(Compound 209) as the di-HCl Salt

A mixture of tert-butyl((S)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate(55 mg, 71.83 μmol),(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (27.05 mg,108 μmol), Sodium carbonate, Pd(dppf)₂, DCM (11.82 mg, 14.34 μmol) indioxane (5 mL) was degassed with N₂ for 5 min. The reaction was heatedat 100° C. overnight. After cooling down to room temperature, solidNa₂SO₄ was added. The mixture was stirred at room temperature for 2 h.The mixture was filtered through a pad of Celite® and Na₂SO₄, washedwith DCM, and then concentrated. The residue was purified by silica gelcolumn chromatography to give tert-butyl((S)-8-((4′-(((tert-butoxycarbonyl)amino)methyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate.LCMS m/z=892.6 [M+H]⁺.

tert-Butyl((S)-8-((4′-(((tert-butoxycarbonyl)amino)methyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(2-fluoro-3-(methylsulfonyl)phenoxy)-2-hydroxypropyl)carbamatefrom the previous step was dissolved in DCM (5 mL). Then HCl (4N indioxane, 180 μL) was added. The reaction was stirred at room temperatureuntil completion. The mixture was concentration. The residue waspurified by prep-HPLC. The combined fractions were added HCl (4N indioxane, 200 μL) and lyophilized to give the title compound (27.5 mg,50% yield) as a white foam. LCMS m/z=692.4 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.49 (t, J=7.07 Hz, 3H), 1.60-1.70 (m, 1H), 1.78-1.93 (m,4H), 2.37 (dd, J=13.64, 8.34 Hz, 1H), 3.07-3.22 (m, 4H), 3.24 (s, 3H),3.51-3.63 (m, 2H), 3.94 (dd, J=10.11, 4.04 Hz, 1H), 4.01-4.09 (m, 1H),4.09-4.33 (m, 8H), 7.30 (d, J=8.59 Hz, 1H), 7.35 (td, J=8.08, 1.52 Hz,1H), 7.47-7.58 (m, 4H), 7.70 (d, J=8.34 Hz, 2H), 7.88 (dd, J=8.59, 2.53Hz, 1H), 8.08 (d, J=2.53 Hz, 1H).

Example 1.57 Preparation of(2S)-1-(8-(Chroman-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol(Compound 28). (Method J) Step A: Preparation of(2S)-1-(1-Oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol

From (S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane and benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, the title compoundwas prepared using a method similar to the ones described in Method A,Step A and C. LCMS m/z=385.2 [M+H]⁺.

Step B: Preparation of(2S)-1-(8-(Chroman-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol(Compound 28)

To a solution of(2S)-1-(1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol(10 mg, 26.01 μmol) and DIEA (9.060 μl, 52.02 μmol) in dioxane (0.4 mL)was added chroman-6-sulfonyl chloride (7.26 mg, 31.21 μmol). Thereaction mixture was stirred overnight at room temperature for 16 h. Thereaction was quenched with water then purified via mass directedprep-HPLC. Collected fractions were lyophilized to give the titlecompound (9.1 mg, 50% yield). LCMS m/z=581.2 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.66 (td, J=10.99, 4.17 Hz, 1H), 1.76-1.90 (m, 4H),1.99-2.06 (m, 2H), 2.31 (ddd, J=13.83, 8.27, 2.40 Hz, 1H), 2.63-2.78 (m,2H), 2.85 (t, J=6.44 Hz, 2H), 3.11 (s, 3H), 3.13-3.20 (m, 1H), 3.25-3.42(m, 3H), 3.89 (td, J=8.59, 5.81 Hz, 1H), 3.96-4.08 (m, 2H), 4.11 (dd,J=4.93, 1.64 Hz, 2H), 4.21-4.30 (m, 3H), 6.90 (d, J=8.34 Hz, 1H),7.26-7.34 (m, 1H), 7.43-7.48 (m, 2H), 7.50 (t, J=1.26 Hz, 1H), 7.56 (d,J=5.05 Hz, 2H).

Example 1.58 Preparation of(3-((S)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-yl)(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanone(Compound 64). (Method K) Step A: Preparation of tert-Butyl((S)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

tert-Butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(15 mg, 30.95 μmol),4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid (7.18 mg,37.14 μmol), HATU (14.12 mg, 37.14 μmol) and triethylamine in DMF (1M,61.91 μL, 61.91 μmol) solution were added in 5 mL scintillation vialfollowing by addition of DMF (1 mL). The reaction mixture was heated at70° C. for 16 h. The reaction mixture was filtered and purified by massdirect pre-HPLC. The collected fractions were lyophilized to give thetitle compound. LCMS m/z=660.6 [M+H]⁺.

Step B: Preparation of(3-((S)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-yl)(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methanone(Compound 64) as the HCl Salt

To a solution of tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamatein ACN (3 mL) was added HCl (4N in dioxane, 100 μL). The reaction wasstirred for 4 h. The mixture was concentrated. The residue wastriturated with hexane to give the title compound (11 mg, 60% yield).LCMS m/z=560.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61 (t, J=10.36Hz, 1H), 1.69-1.86 (m, 3H), 1.91 (dt, J=13.58, 5.72 Hz, 1H), 2.40 (ddd,J=13.64, 8.21, 2.15 Hz, 1H), 2.92 (s, 3H), 3.12 (s, 3H), 3.19 (dt,J=12.82, 9.25 Hz, 1H), 3.32-3.38 (m, 2H), 3.40-3.53 (m, 2H), 3.95-4.20(m, 6H), 4.22-4.33 (m, 3H), 6.70 (d, J=8.34 Hz, 1H), 6.78 (d, J=2.02 Hz,1H), 6.91 (dd, J=8.34, 2.02 Hz, 1H), 7.32 (td, J=3.73, 1.89 Hz, 1H),7.52 (t, J=1.26 Hz, 1H), 7.57 (d, J=5.31 Hz, 2H).

Example 1.59 Preparation of(2S)-1-(3-(Fluoromethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 86)

To a solution of8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine (14.07mg, 40.61 μmol) was dissolved in EtOH (0.6 mL) was added(S)-2-((3-((fluoromethyl)sulfonyl)phenoxy) methyl)oxirane (5 mg, 20.30μmol), pre-dissolved in EtOH (0.3 mL). The reaction was stirred at 90°C. overnight. The next day, the solvent was removed, and the residue waspurified by PrepLC/MS to give the title compound (6.2 mg, 8.7 μmol,42.8% yield) as a solid. LCMS m/z=593.4 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.55-1.65 (m, 1H), 1.66-1.85 (m, 4H), 2.07-2.19 (m, 1H),2.58-2.75 (m, 2H), 2.86-3.02 (m, 1H), 3.03-3.16 (m, 1H), 3.27-3.43 (m,3H), 3.65-3.74 (m, 1H), 3.80-3.94 (m, 2H), 4.01-4.07 (m, 2H), 4.07-4.16(m, 1H), 5.66 (s, 1H), 5.78 (s, 1H), 7.35-7.44 (m, 2H), 7.54 (d, J=7.96Hz, 1H), 7.64 (t, J=7.98 Hz, 1H), 7.67-7.80 (m, 3H), 8.09 (d, J=8.04 Hz,1H), 8.18 (d, J=8.72 Hz, 1H), 8.21 (d, J=7.92 Hz, 1H), 8.44 (s, 1H),8.73 (bs, 2H).

Example 1.60 Preparation of(S)-1-((R)-8-(4′-(1-Aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 199) Step A: Preparation of tert-Butyl((R)-8-((3-Bromo-4-methoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

From tert-butyl((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate and3-bromo-4-methoxybenzene-1-sulfonyl chloride, the title compound wasprepared in a similar method described in Method F, Step D. LCMSm/z=789.4/791.4 [M+H]⁺.

Step B: Preparation of tert-Butyl((R)-8-((4′-(1-((tert-Butoxycarbonyl)amino)cyclopropyl)-6-methoxy-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

From tert-butyl((R)-8-((3-bromo-4-methoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamateand (4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,the title compound was prepared in a similar method described in MethodF, Step E. LCMS m/z=942.6 [M+H]⁺.

Step C: Preparation of(S)-1-((R)-8-(4′-(1-Aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 199)

From tert-butyl((R)-8-((4′-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-6-methoxy-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate, the title compound wasprepared in a similar method described in Method F, Step F. LCMSm/z=742.8 [M+H]⁺; ¹H NMR (400 M Hz, CD₃OD) δ ppm 1.07-1.10 (m, 2H),1.33-1.37 (m, 2H), 1.40-1.44 (m, 2H), 1.48-1.51 (q, J=3.77 Hz, 2H),1.63-1.70 (m, 1H), 1.81-1.91 (m, 4H), 2.33 (dd, J=8.13, 13.55 Hz, 1H),2.69-2.80 (m, 2H), 3.16 (dd, J=9.75, 13.00 Hz, 1H), 3.28 (d, J=2.96 Hz,1H), 3.39-3.46 (m, 2H), 3.72 (s, 2H), 3.90 (s, 3H), 3.93 (d, J=3.52 Hz,1H), 3.99-4.07 (m, 2H), 4.09-4.14 (m, 2H), 4.25-4.30 (m, 1H), 7.30 (m,1H), 7.31 (d, J=8.64 Hz, 1H), 7.47-7.60 (m, 7H), 7.63 (d, J=2.32 Hz,1H), 7.78 (dd, J=2.52, 9.00 Hz, 1H).

Example 1.61 Preparation of(S)-1-((R)-8-(4-Ethoxy-4′-((isopropylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 165). (Method L) Step A: Preparation oftert-Butyl((R)-8-((5-Bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

From(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, and5-bromo-2-ethoxybenzene-1-sulfonyl chloride, the title compound wasprepared using a similar method to the one described in Method F, StepA, B, C, and D.

Step B: Preparation of tert-Butyl((R)-8-((4-Ethoxy-4′-formyl-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl((R)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (25 mg, 31.10 μmol) in EtOH (0.6 mL)/H₂O (0.300 mL)were added potassium carbonate (9.457 mg, 68.43 μmol), Pd(dppf)2, DCM(255.9 μg, 0.311 μmol) and (4-formylphenyl)boronic acid (6.529 mg, 43.54μmol). The reaction was degassed for 5 min before heated to 80° C. for 1h. The mixture was diluted with EtOAc, washed with water (3×) and brine,dried over Na₂SO₄ and concentrated. The residue was purified by silicagel column chromatography to give the title compound (21 mg, 78.2%yield) as a white solid. LCMS m/z=829.6 [M+H]⁺; ¹H NMR (400 M Hz, CDCl₃)δ ppm 1.03-1.09 (m, 2H), 1.48 (s, 9H), 1.52 (spt, 3H), 1.59-1.63 (m,2H), 1.63-1.69 (m, 2H), 1.71-1.79 (m, 2H), 1.81-1.91 (m, 2H), 2.08 (dd,J=13.01, 8.72 Hz, 1H), 3.05-3.18 (m, 2H), 3.35-3.45 (m, 1H), 3.45-3.51(m, 1H), 3.57-3.65 (m, 2H), 3.66 (s, 2H), 3.77-3.85 (m, 1H), 3.88-3.94(m, 1H), 3.99 (t, J=5.18 Hz, 2H), 4.09-4.17 (m, 1H), 4.22 (q, J=6.99 Hz,2H), 4.56-4.65 (m, 1H), 7.08 (d, J=8.84 Hz, 1H), 7.15-7.19 (m, 1H),7.39-7.42 (m, 1H), 7.45-7.52 (m, 2H), 7.73 (d, J=8.34 Hz, 2H), 7.76 (dd,J=8.59, 2.53 Hz, 1H), 7.95 (d, J=8.34 Hz, 2H), 8.20 (d, J=2.53 Hz, 1H),10.05 (s, 1H)

Step C: Preparation of tert-Butyl((R)-8-((4-Ethoxy-4′-((isopropylamino)methyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl((R)-8-((4-ethoxy-4′-formyl-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (21 mg, 24.32 μmol, 78.2%) in dichloroethane (1 mL) were addedacetic acid (8.894 μL 0.156 mmol), isopropylamine (12.73 μL 0.156 mmol)and stirred for 30 min. Sodium triacetoxyborohydride (13.18 mg, 62.21μmol) was added in one portion and stirred for 2 h at room temperatureand at 60° C. overnight. The reaction was quenched with water andextracted with DCM (×3). The combined organic layer was washed withbrine, filtered, dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography using EtOAc to give thetitle compound (18.28 mg, 67% yield) as a white solid. LCMS m/z=872.8[M+H]⁺; ¹H NMR (400 M Hz, CDCl₃) δ ppm 1.03-1.08 (m, 2H), 1.14 (d,J=6.32 Hz, 6H), 1.20-1.36 (m, 2H) 1.47 (s, 9H), 1.49 (t, J=6.82 Hz, 3H),1.57-1.62 (m, 2H), 1.62-1.67 (m, 1H), 1.71-1.77 (m, 1H), 1.78-1.89 (m,2H), 2.07 (dd, J=12.88, 8.84 Hz, 1H), 2.86-2.94 (m, 1H), 3.04-3.16 (m,2H), 3.35-3.44 (m, 1H), 3.45-3.51 (m, 1H), 3.54-3.65 (m, 2H), 3.66 (s,2H), 3.83 (s, 2H), 3.87-3.92 (m, 1H), 3.95-4.04 (m, 2H), 4.09-4.23 (m,1H), 4.16-4.22 (m, 2H), 4.54-4.65 (m, 1H), 7.03 (d, J=8.59 Hz, 1H), 7.16(dt, J=7.01, 2.43 Hz, 1H), 7.38-7.42 (m, 3H), 7.44-7.54 (m, 4H), 7.68(dd, J=8.59, 2.53 Hz, 1H), 8.11 (d, J=2.27 Hz, 1H).

Step D: Preparation of(S)-1-((R)-8-(4-Ethoxy-4′-((isopropylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 165)

To a solution of tert-butyl((R)-8-((4-ethoxy-4′-((isopropylamino)methyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate(18.28 mg, 20.84 μmol) in MeOH (1 mL) was added HCl in dioxane (0.156mL, 0.622 mmol) at room temperature. The reaction was allowed to standat room temperature until the Boc-group was cleaved. Then the solventwas removed and the residue was lyophilized to give the title compound(12 mg, 67% yield) as a white solid. LCMS m/z=772.6 [M+H]⁺; ¹H NMR (400M Hz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.41 (d, J=6.57 Hz, 6H), 1.49 (t,J=6.95 Hz, 3H), 1.49-1.52 (m, 2H), 1.60-1.70 (m, 1H), 1.76-1.93 (m, 3H),2.37 (dd, J=13.77, 8.21 Hz, 1H), 3.06-3.23 (m, 3H), 3.24-3.27 (m, 1H),3.43-3.50 (m, 1H), 3.52-3.56 (m, 1H), 3.56-3.63 (m, 2H), 3.64-3.69 (m,1H), 3.72 (s, 2H), 3.73-3.75 (m, 1H), 3.94-3.98 (m, 1H), 4.01-4.07 (m,1H), 4.08-4.15 (m, 2H), 4.23-4.31 (m, 3H), 4.25 (s, 2H), 7.26-7.32 (m,2H), 7.46-7.51 (m, 1H), 7.51-7.57 (m, 2H), 7.59 (d, J=8.34 Hz, 2H), 7.72(d, J=8.34 Hz, 2H), 7.88 (dd, J=8.72, 2.40 Hz, 1H), 8.09 (d, J=2.53 Hz,1H).

Example 1.62 Preparation of(S)-1-((R)-8-(1,4-Dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 222) Step A: Preparation oftert-Butyl ((S)-2-Hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

From (S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanoland (R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, thetitle compound was prepared using a similar method to the one describedin Method F, Step A, B, C.

Step B: Preparation of tert-Butyl((R)-8-((5-Bromo-6-chloropyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate (200 mg,0.370 mmol) in CH₂Cl₂ (3.0 mL) was added DIEA (0.155 mL, 0.888 mmol)followed by addition of 5-bromo-6-chloropyridine-3-sulfonyl chloride(0.129 g, 0.444 mmol) at 0° C. The reaction was stirred at roomtemperature overnight. The mixture was concentrated. The residue waspurified by silica gel column chromatography to give the title compound(230 mg, 73.7% yield) as a white solid. LCMS m/z=796.4 [M+H]⁺.

Step C: Preparation of tert-Butyl((R)-8-((1,4-Dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate

To a mixture of tert-Butyl((R)-8-((5-bromo-6-chloropyridin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (25 mg, 31.44 μmol), potassium carbonate (13.04mg, 94.32 μmol) in DMF (0.8 mL) was addedN¹,N²-dimethylethane-1,2-diamine (3.326 mg, 37.73 μmol) in a microwavevial. The reaction was heated at 160° C. for 15 min under microwaveirradiation. The mixture was filtered and washed with MeOH. The filtratewas concentrated and purified by silica gel column chromatography togive the title compound (21 mg, 83.0% yield) as white solid. LCMSm/z=766.6 [M+H]⁺.

Step D: Preparation of(S)-1-((R)-8-(1,4-Dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 222)

To a solution of tert-butyl((R)-8-((1,4-dimethyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)carbamate (21 mg, 26.10 μmol, 83.0%) wasdissolved in MeOH (0.2 mL) was added HCl in dioxane (0.118 mL, 0.472mmol) at room temperature. The reaction was allowed to stand at roomtemperature until the Boc-group was cleaved (˜30 min). The mixture wasconcentrated and the residue was lyophilized to give the title compound(19 mg, 25.49 μmol, 81.1% yield) as a white solid. LCMS m/z=666.4[M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.09-1.13 (m, 2H), 1.50-1.54 (m,2H), 1.66-1.75 (m, 1H), 1.84-1.99 (m, 4H), 2.39 (dd, J=13.64, 8.34 Hz,1H), 2.84-2.92 (m, 1H), 2.91-2.98 (m, 1H), 3.04 (s, 3H), 3.20 (dd,J=12.76, 9.47 Hz, 1H), 3.34-3.37 (m, 1H), 3.36 (s, 3H), 3.45-3.49 (m,2H), 3.49-3.57 (m, 2H), 3.74 (s, 2H), 3.85 (t, J=5.18 Hz, 2H), 3.92-3.99(m, 1H), 4.02-4.12 (m, 2H), 4.11-4.19 (m, 2H), 4.26-4.34 (m, 1H), 6.82(d, J=1.52 Hz, 1H), 7.32 (ddd, J=7.83, 2.53, 1.52 Hz, 1H), 7.48-7.51 (m,1H), 7.51-7.54 (m, 1H), 7.56 (d, J=7.83 Hz, 1H), 7.60 (d, J=1.77 Hz,1H).

Example 1.63 Preparation of(S)-1-((S)-8-(4′-(Aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol(Compound 160). (Method M) Step A: Preparation of tert-Butyl((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

From (S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane and(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, the titlecompound was prepared using a similar method to the one described inMethod A, Step A, B, and C.

Step B: Preparation of tert-Butyl((S)-8-((5-Bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate

To a solution of tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(177 mg, 0.35 mmol) in DCM (15 mL) was added DIEA (0.17 mL, 0.98 mmol)and 5-bromo-2-ethoxybenzene-1-sulfonyl chloride (0.14 g, 0.45 mmol). Thereaction was stirred at room temperature overnight. After the reactionwas completed, the mixture was concentrated. The residue was purified bysilica gel column chromatography to give the title compound (233 mg, 87%yield) as a colorless glass. LCMS m/z=773.6 [M]⁺; ¹H NMR (400 MHz,CD₃OD) δ ppm 1.03-1.10 (m, 2H), 1.19-1.25 (m, 2H), 1.43-1.47 (m, 12H),1.50-1.63 (m, 1H), 1.71 (ddd, J=13.39, 3.92, 3.66 Hz, 1H), 1.81 (t,J=4.55 Hz, 2H), 1.99-2.13 (m, 2H), 2.62-2.71 (m, 1H), 3.06-3.22 (m, 2H),3.24-3.29 (m, 1H), 3.36-3.50 (m, 2H), 3.55 (dd, J=14.65, 4.80 Hz, 1H),3.80 (dd, J=8.84, 7.33 Hz, 1H), 3.92 (t, J=8.21 Hz, 1H), 3.98-4.03 (m,1H), 4.04-4.10 (m, 1H), 4.11-4.22 (m, 3H), 4.49 (t, J=7.71 Hz, 1H), 7.12(d, J=9.09 Hz, 1H), 7.28 (ddd, J=8.02, 2.59, 1.26 Hz, 1H), 7.44 (d,J=2.27 Hz, 1H), 7.47 (dt, J=8.0, 1.39 Hz, 1H), 7.52 (t, J=8.08 Hz, 1H),7.69 (dd, J=8.84, 2.53 Hz, 1H), 7.90 (d, J=2.53 Hz, 1H).

Step C: Preparation of tert-Butyl((S)-8-((4′-(((tert-Butoxycarbonyl)amino)methyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate

A solution of tert-butyl((S)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate (233mg, 0.30 mmol), Pd(dppf)₂, DCM (24.77 mg, 30.11 μmol), sodium carbonate(0.33 mL, 0.66 mmol) and(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (90.73 mg,0.36 mmol) in dioxane (12 mL) was degassed with N₂ for 10 min. Thereaction was heated at 100° C. for 18 h. After cooling down to roomtemperature, it was diluted with IPA/DCM (20%) and washed water. Theaqueous layer was back extracted with IPA/DCM (20%, 2×). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (126 mg, 47% yield). LCMS m/z=900.8 [M+H]⁺.

Step D: Preparation of(S)-1-((S)-8-(4′-(Aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol(Compound 160)

To a solution of tert-butyl((S)-8-((4′-(((tert-butoxycarbonyl)amino)methyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)carbamate(126 mg, 0.16 mmol) in ACN (4 mL) was added HCl (4N in dioxane, 0.3 mL,1.2 mmol). The reaction was stirred at room temperature for 3 h. Afterthe reaction was completed, the mixture was concentrated. The residuewas purified by prep-HPLC to give TFA salt of the title compound. TheTFA salt was converted to the HCl salt of the title compound (68.7 mg,30% yield). LCMS m/z=700.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm1.03-1.10 (m, 2H), 1.19-1.25 (m, 2H), 1.49 (t, J=6.95 Hz, 3H), 1.60-1.70(m, 1H), 1.77-1.85 (m, 1H), 1.85-1.94 (m, 3H), 2.37 (dd, J=13.64, 8.34Hz, 1H), 2.68 (tt, J=7.96, 4.80 Hz, 1H), 3.06-3.23 (m, 3H), 3.32-3.37(m, 1H), 3.51-3.64 (m, 2H), 3.91-3.97 (m, 1H), 4.00-4.08 (m, 1H),4.09-4.15 (m, 3H), 4.17 (s, 2H), 4.22-4.33 (m, 3H), 7.27-7.33 (m, 2H),7.46 (t, J=2.27 Hz, 1H), 7.50-7.59 (m, 4H), 7.66-7.73 (m, 2H), 7.88 (dd,J=8.72, 2.40 Hz, 1H), 8.08 (d, J=2.53 Hz, 1H).

Example 1.64 Preparation of(S)-1-(3-(Cyclopropylsulfonyl)phenoxy)-3-((R)-8-(3-methyl-3H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 279). (Method N) Step A: Preparation of tert-Butyl((S)-3-(3-(Cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(20 mg, 39.17 μmol) in THF (4 mL) was added DIEA (13.64 μL, 78.33 μmol),followed by addition of 3-methyl-3H-imidazo[4,5-b]pyridine-6-sulfonylchloride (10.89 mg, 47.00 μmol). The reaction was stirred for 2 h. Themixture was diluted with EtOAc, washed with water (3×) and brine, andconcentrated. The residue was purified by silica gel columnchromatography to give a white solid. LCMS m/z=706.4 [M+H]⁺; ¹H NMR (400M Hz, CD₃OD) δ ppm 1.02-1.08 (m, 2H), 1.18-1.24 (m, 2H), 1.43 (s, 9H),1.60-1.68 (m, 1H), 1.73-1.88 (m, 4H), 1.99-2.04 (m, 1H), 2.71-2.82 (m,2H), 3.20 (m, 1H), 3.38-3.44 (m, 2H), 3.48-3.52 (m, 2H), 3.76-3.80 (m,1H), 3.89-3.92 (m, 1H), 3.95-3.97 (m, 1H), 3.99 (s, 3H), 4.01-4.04 (m,1H), 4.09-4.14 (m, 1H), 4.42-4.50 (m, 1H), 7.23-7.26 (m, 1H), 7.40-7.41(m, 1H), 7.47 (dt, J=7.96, 1.49 Hz, 1H), 7.52 (t, J=7.88 Hz, 1H), 8.40(d, J=1.96 Hz, 1H), 8.55 (s, 1H), 8.80 (d, J=1.96 Hz, 1H).

Step B: Preparation of(S)-1-(3-(Cyclopropylsulfonyl)phenoxy)-3-((R)-8-(3-methyl-3H-imidazo[4,5-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol(Compound 279) as the di-HCl Salt

To a solution of tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(13 mg, 18.42 μmol) in EtOAc (10 mL) was added HCl (671.5 μg, 18.42μmol). The reaction was stirred for 3 h. The mixture was concentrated togive the title compound as a white solid. LCMS m/z=606.6 [M+H]⁺; ¹H NMR(400 M Hz, CD₃OD) δ ppm 1.03-1.09 (m, 2H), 1.19-1.24 (m, 2H), 1.65-1.73(m, 1H), 1.79-1.86 (m, 1H), 1.88-1.98 (m, 1H), 2.32 (dd, J=7.39, 12.94Hz, 1H), 2.63-2.69 (m, 1H), 2.70-2.82 (m, 2H), 3.16 (d, J=8.53 Hz, 1H),3.25-3.29 (m, 1H), 3.32-3.37 (m, 1H), 3.50-3.59 (m, 3H), 3.64-3.69 (m,1H), 3.83-3.90 (m, 1H), 4.00 (d, J=6.64 Hz, 2H), 4.04 (s, 3H), 4.09 (dd,J=3.42, 4.95 Hz, 2H), 4.20-4.26 (m, 1H), 7.27-7.30 (m, 1H), 7.44 (dd,J=1.67, 2.39 Hz, 1H), 7.51 (dt, J=1.56, 7.81 Hz, 1H), 7.55 (t, J=7.82Hz, 1H), 8.48 (d, J=1.88 Hz, 1H), 8.85 (s, 1H), 8.88 (d, J=1.92 Hz, 1H).

Example 1.65 Preparation of1-Ethyl-3-((S)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 338) Step A: Preparation of (S)-Benzyl3-(((S)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

A solution of (S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (0.10 g,0.44 mmol) and (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.25 g, 0.88 mmol) inEtOH (8.76 mL) was heated at 70° C. for 1 day. After cooling down toroom temperature, the mixture was concentrated to give the titlecompound which was used in the next step without further purification.LCMS m/z=519.4 [M+H]⁺.

Step B: Preparation of (S)-Benzyl3-((tert-Butoxycarbonyl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of (S)-benzyl3-(((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(from the previous step) in DCM (8 mL) was added DIEA (0.23 mL, 1.31mmol) and (Boc)₂O (0.29 g, 1.31 mmol). The reaction was stirred roomtemperature for 16 h. The mixture was extracted with water and brine.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography to give the title compound(174.0 mg, 64.2%). LCMS m/z=619.4 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm1.47 (s, 9H), 1.48-1.54 (m, 1H), 1.59-1.68 (m, 1H), 1.69-1.77 (m, 2H),2.04-2.15 (m, 2H), 3.11 (s, 3H), 3.40 (bs, 2H), 3.57 (dd, J=14.65, 4.80Hz, 1H), 3.65 (t, J=13.01 Hz, 2H), 3.84 (dd, J=8.97, 7.20 Hz, 1H),3.93-4.12 (m, 4H), 4.16 (ddd, J=7.26, 4.80, 4.61 Hz, 1H), 4.47-4.59 (m,1H), 5.11 (s, 2H), 7.27-7.34 (m, 2H), 7.34-7.37 (m, 4H), 7.48-7.58 (m,3H).

Step C: Preparation of tert-Butyl((S)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

(S)-Benzyl3-((tert-butoxycarbonyl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (162 mg, 0.26 mmol) wasdissolved in MeOH (8 mL) under N₂ followed by addition of Pd/C (30 mg,28.12 umol). The reaction was placed under H₂ balloon and stirred atroom temperature overnight. The mixture was filtered through a pad ofCelite® and washed with MeOH then concentrate to give the title compound(120 mg, 88.1%) as yellow solid. This material was used in the next stepwithout further purification. LCMS m/z=485.4 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 1.50 (s, 9H), 1.53-1.68 (m, 1H), 1.69-1.77 (m, 3H), 1.80(t, J=5.31 Hz, 1H), 2.04-2.19 (m, 1H), 2.31 (s, 1H), 2.38-2.56 (m, 3H),2.79 (dd, J=11.12, 5.81 Hz, 1H), 2.95-3.04 (m, 1H), 3.06 (s, 3H), 3.49(d, J=2.53 Hz, 2H), 3.80 (ddd, J=9.54, 6.25, 3.16 Hz, 1H), 3.89-4.02 (m,2H), 4.02-4.08 (m, 1H), 4.12 (t, J=3.54 Hz, 1H), 4.56-4.69 (m, 1H), 7.20(ddd, J=8.08, 2.53, 1.01 Hz, 1H), 7.43-7.52 (m, 2H), 7.53-7.58 (m, 1H).

Step D: Preparation of tert-Butyl((S)-8-((1-Ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(120 mg, 0.25 mmol) in CH₂Cl₂ (2 mL) at room temperature was added DIEA(86.26 μl, 0.50 mmol) then 1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonylchloride (0.10 g, 0.37 mmol). The reaction was stirred at roomtemperature overnight. The mixture was diluted with DCM then washed withwater and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography to givethe title compound (92 mg, 51.6%) as a yellow gum. LCMS m/z=720.6[M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.45 (s, 9H), 1.52 (t, J=7.20 Hz,3H), 1.56-1.63 (m, 1H), 1.72 (dt, J=13.58, 4.33 Hz, 1H), 1.83 (t, J=5.81Hz, 2H), 1.98-2.10 (m, 2H), 3.08 (s, 3H), 3.20-3.29 (m, 3H), 3.39-3.57(m, 3H), 3.78 (dd, J=8.84, 7.07 Hz, 1H), 3.91 (t, J=8.21 Hz, 1H),3.97-4.09 (m, 2H), 4.10-4.18 (m, 1H), 4.48 (q, J=7.16 Hz, 3H), 7.27 (dt,J=7.39, 2.24 Hz, 1H), 7.45-7.52 (m, 3H), 7.56 (ddd, J=8.15, 4.99, 3.03Hz, 1H), 7.85-7.89 (m, 2H), 8.39 (d, J=7.83 Hz, 1H), 8.66 (s, 1H).

Step E: Preparation of1-Ethyl-3-((S)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 338)

tert-Butyl((S)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate(92 mg, 0.13 mmol) was stirred in TFA/DCM (1:3, 2 mL) at roomtemperature. After the reaction completed, solvent was removed. Theresidue was purified by prep-HPLC. The obtained material was dissolvedin water and neutralized with saturated NaHCO₃ then extracted withIPA/DCM (10%, 2×100 mL). The organic layer was washed with brined, driedover Na₂SO₄, filtered and concentrated. The free base was dissolved inacetone and added HCl (4N, 0.2 mL). The resulting solution was stirredfor 2 h then concentrated to give the title compound (63.5 mg, 75.1%).LCMS m/z=620.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38 (t, J=7.07Hz, 3H), 1.51-1.62 (m, 1H), 1.62-1.71 (m, 1H), 1.72-1.86 (m, 3H), 2.18(dd, J=13.01, 8.46 Hz, 1H), 2.90-3.01 (m, 1H), 3.05-3.20 (m, 3H), 3.21(s, 3H), 3.35-3.42 (m, 2H), 3.77-3.83 (m, 1H), 3.87-4.00 (m, 2H), 4.07(d, J=5.05 Hz, 2H), 4.12-4.22 (m, 1H), 4.46 (q, J=6.82 Hz, 2H), 5.91(bs, 1H), 7.30 (dd, J=7.71, 2.15 Hz, 1H), 7.44 (t, J=1.77 Hz, 1H),7.49-7.56 (m, 2H), 7.57 (t, J=7.83 Hz, 1H), 7.82-7.90 (m, 2H), 8.24 (d,J=1.26 Hz, 1H), 8.63 (s, 1H), 8.85 (bs, 1H), 9.02 (bs, 1H).

Example 1.66 Preparation of1-Ethyl-3-((S)-3-((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 296) Step A: Preparation of(R)-2-((3-(Methylsulfonyl)phenoxy)methyl)oxirane

To a solution of 3-(methylsulfonyl)phenol (1.34 g, 6.98 mmol) in acetone(34.87 mL) was added potassium carbonate (1.93 g, 13.95 mmol). Thereaction mixture was stirred at room temperature for 10 min followed byaddition of (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.90 g, 6.98mmol). The reaction mixture was heated at 70° C. overnight. Aftercooling down to room temperature, the reaction mixture was filteredthrough a pad of Celite® and washed with acetone then concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound (1.43 g, 88.0% yield) as colorless oil then solidifiedafter standing at room temperature. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.79(dd, J=4.93, 2.65 Hz, 1H), 2.94 (t, J=4.04 Hz, 1H), 3.06 (s, 3H),3.35-3.41 (m, 1H), 4.00 (dd, J=10.99, 5.94 Hz, 1H), 4.37 (dd, J=11.12,2.78 Hz, 1H), 7.22 (ddd, J=8.08, 2.53, 1.01 Hz, 1H), 7.48 (t, J=2.27 Hz,1H), 7.50 (d, J=8.08 Hz, 1H), 7.54-7.58 (m, 1H).

Step B: Preparation of (S)-Benzyl3-(((R)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

A solution of (R)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (100 mg,0.44 mmol) and (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.25 g, 0.88 mmol) inEtOH (8.8 mL) was heated at 70° C. overnight. After cooling down to roomtemperature, the mixture was concentrated. The residue was re-dissolvedin DCM and washed with water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated to give the title compound which wasused directly in the next step. LCMS m/z=519.6 [M+H]⁺.

Step C: Preparation of (S)-Benzyl3-((tert-Butoxycarbonyl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of (S)-benzyl3-(((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(326 mg, 0.63 mmol) in DCM (8.8 mL) at room temperature was added DIEA(0.15 mL, 0.88 mmol) and (Boc)₂O (0.19 g, 0.88 mmol). The reaction wasstirred at room temperature until completion. The mixture was dilutedwith DCM and washed with water and brine. The organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography to give the title compound (176 mg, 64.9%) as awhite foam. LCMS m/z=619.6 [M+H]⁺; ¹H NMR (400 MHz, MeOD) δ ppm1.40-1.52 (m, 11H), 1.59-1.74 (m, 3H), 1.80 (dd, J=12.88, 8.08 Hz, 1H),2.06 (dd, J=12.76, 8.46 Hz, 1H), 3.03 (s, 3H), 3.17-3.29 (m, 1H),3.33-3.42 (m, 2H), 3.50 (dd, J=14.65, 3.79 Hz, 1H), 3.59-3.69 (m, 2H),3.89-4.00 (m, 4H), 4.49-4.60 (m, 1H), 5.07 (s, 2H), 7.18 (ddd, J=6.69,2.65, 2.53 Hz, 1H), 7.25-7.35 (m, 5H), 7.42 (t, J=1.77 Hz, 1H),7.46-7.51 (m, 2H).

Step D: Preparation of tert-Butyl((R)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of (S)-benzyl3-((tert-butoxycarbonyl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(176 mg, 0.28 mmol) in MeOH (10 mL) was added Palladium/C (30.27 mg,28.44 nmol). The reaction was placed under H₂ balloon and stirred atroom temperature overnight. The mixture was filtered through a pad ofCelite® and washed with MeOH. The filtrate was concentrated to give thetitle compound (137 mg, 68.9%) as a yellow foam. This material will beused in the next step without further purification. LCMS m/z=485.4[M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.47 (s, 9H), 1.52-1.81 (m, 4H),1.86 (dd, J=12.63, 8.34 Hz, 1H), 2.06-2.16 (m, 1H), 2.26 (s, 1H),2.38-2.56 (m, 1H), 2.73-2.81 (m, 1H), 2.91-3.03 (m, 1H), 3.12 (s, 3H),3.23-3.29 (m, 1H), 3.56 (ddd, J=14.53, 4.55, 1.89 Hz, 1H), 3.89-3.97 (m,1H), 3.98-4.11 (m, 3H), 4.15-4.22 (m, 1H), 4.55 (dq, J=7.71, 7.54 Hz,1H), 7.27-7.33 (m, 1H), 7.49-7.52 (m, 1H), 7.52-7.59 (m, 2H).

Step E: Preparation of tert-Butyl((S)-8-((1-Ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(73 mg, 0.15 mmol) in CH₂Cl₂ (2 mL) was added DIEA (89.21 μL, 0.51 mmol)and 1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride (82.27 mg,0.18 mmol). The reaction was stirred at room temperature overnight. Nextday, additional tert-butyl((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(23 mg, 0.05 mmol) and DIEA (30 uL, 0.17 mmol) were added. The reactionwas stirred for another 5 h then concentrated. The residue was purifiedby silica gel column chromatography to give the title compound (67 mg,61.8%) as a clear glass. LCMS m/z=720.6 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD)δ ppm 1.45 (s, 9H), 1.52 (t, J=7.20 Hz, 3H), 1.57-1.66 (m, 1H),1.69-1.77 (m, 1H), 1.77-1.82 (m, 2H), 1.85 (dd, J=12.76, 8.21 Hz, 1H),2.07 (dd, J=12.88, 8.59 Hz, 1H), 3.08 (s, 3H), 3.20-3.30 (m, 3H),3.41-3.49 (m, 2H), 3.50-3.56 (m, 1H), 3.88 (dd, J=7.58, 1.77 Hz, 1H),3.95-4.02 (m, 2H), 4.03-4.08 (m, 1H), 4.12-4.19 (m, 1H), 4.44-4.56 (m,3H), 7.27 (ddd, J=7.64, 2.08, 1.89 Hz, 1H), 7.45-7.52 (m, 3H), 7.53-7.58(m, 1H), 7.85-7.91 (m, 2H), 8.39 (dt, J=7.89, 0.85 Hz, 1H), 8.65 (s,1H).

Step F: Preparation of1-Ethyl-3-((S)-3-((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 296)

To a solution of tert-butyl((S)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate(67 mg, 93.07 μmol) in CH₂Cl₂ (1.50 mL) was added TFA (0.5 mL). Theresulting solution was stirred at ambient temperature for 2 h thenconcentrated. The residue was purified by prep-HPLC to give the titlecompound as TFA salt which was then converted to the HCl salt (53.5 mg,87.6%) as a solid. LCMS m/z=620.4 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.38 (t, J=7.07 Hz, 3H), 1.52-1.61 (m, 1H) 1.62-1.70 (m, 1H),1.71-1.82 (m, 3H), 2.20 (dd, J=12.88, 7.83 Hz, 1H), 2.94-3.05 (m, 1H),3.05-3.20 (m, 4H), 3.21 (s, 3H), 3.26-3.42 (m, 1H), 3.78-3.86 (m, 1H),3.88-3.99 (m, 2H), 4.07 (d, J=5.05 Hz, 2H), 4.12-4.21 (m, 1H), 4.46 (q,J=7.24 Hz, 2H), 5.90 (d, J=4.80 Hz, 1H), 7.30 (dd, J=8.08, 1.77 Hz, 1H),7.44 (t, J=1.52 Hz, 1H), 7.49-7.56 (m, 2H), 7.59 (t, J=7.83 Hz, 1H),7.82-7.91 (m, 2H), 8.24 (dd, J=7.33, 1.26 Hz, 1H), 8.63 (s, 1H), 8.88(bs, 2H).

Example 1.67 Preparation of1-Ethyl-3-((R)-3-((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 337) Step A: Preparation of (R)-Benzyl3-(((R)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

A solution of (R)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane (100 mg,0.44 mmol) and (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (0.25 g, 0.88 mmol) inEtOH (8.8 mL) was heated at 70° C. overnight. After cooling down to roomtemperature, the mixture was concentrated. The residue was added ethylacetate then washed with water and brine. The organic layer was driedover Na₂SO₄, filtered and concentrated to give the title compound whichwas used in the next step without purification. LCMS m/z=519.6 [M+H]⁺.

Step B: Preparation of (R)-Benzyl3-((tert-Butoxycarbonyl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

To a solution of (R)-benzyl3-(((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(176 mg, 0.34 mmol) in DCM (8.8 mL) at room temperature were added DIEA(0.15 mL, 0.88 mmol) and (Boc)₂O (0.19 g, 0.88 mmol). The reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with DCM then washed with water and brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography to give the title compound (166 mg, 61.2%) as a whitefoam solid. LCMS m/z=619.6 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.46(s, 9H), 1.48-1.54 (m, 1H), 1.61-1.69 (m, 1H), 1.70-1.77 (m, 2H),2.06-2.14 (m, 2H), 3.11 (s, 3H), 3.34-3.46 (m, 2H), 3.54-3.70 (m, 3H),3.84 (dd, J=8.84, 7.07 Hz, 1H), 3.94-4.11 (m, 3H), 4.13-4.20 (m, 1H),4.48-4.57 (m, 2H), 5.11 (s, 2H), 7.27-7.37 (m, 6H), 7.50 (t, J=1.26 Hz,1H), 7.52-7.58 (m, 2H).

Step C: Preparation of tert-Butyl((R)-2-Hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl) ((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate

To a solution of (R)-benzyl3-((tert-butoxycarbonyl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate(187 mg, 0.30 mmol) in MeOH (10 mL) was added Palladium/C (32.16 mg,30.22 μmol) under nitrogen. The reaction was placed under H₂ balloon andstirred at room temperature overnight. The mixture was filtered througha pad of Celite® then washed with MeOH. The filtrate was concentrated togive the title compound (137 mg, 93.5%) as a white foam. This materialwas used in the next step without further purification. LCMS m/z=485.4[M+H]⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 1.47 (s, 9H), 1.49-1.84 (m, 4H),2.08 (t, J=7.96 Hz, 2H), 2.37-2.66 (m, 2H), 2.67-2.78 (m, 1H), 2.87-3.00(m, 1H), 3.12 (s, 3H), 3.25-3.34 (m, 1H), 3.57 (ddd, J=14.65, 4.80, 1.52Hz, 1H), 3.78-3.85 (m, 1H), 3.95 (ddd, J=8.78, 7.64, 5.56 Hz, 1H),3.99-4.06 (m, 1H), 4.06-4.11 (m, 1H), 4.13-4.21 (m, 1H), 4.46-4.57 (m,1H), 7.30 (dt, J=7.01, 2.43 Hz, 1H), 7.50 (t, J=2.02 Hz, 1H), 7.52-7.58(m, 2H).

Step D: Preparation of tert-Butyl((R)-8-((1-Ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate

To a solution of tert-butyl((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate(137 mg, 0.28 mmol) in CH₂Cl₂ (3 mL) was added DIEA (0.17 mL, 0.96 mmol)and 1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride (0.13 g, 0.28mmol). The reaction was stirred at room temperature overnight thenquenched with water and extracted with IPA/DCM (10%, 2×100 mL). Thecombined organic layers were washed with brine, and dried over Na₂SO₄then filtered. The filtrate was concentrated and purified by silica gelcolumn chromatography to give the title compound as white foam solid(116 mg, 57.0%). LCMS m/z=720.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.32-1.37 (m, 13H), 1.45-1.54 (m, 1H), 1.56-1.64 (m, 1H), 1.67-1.73 (m,2H), 1.92-1.98 (m, 1H), 3.04-3.22 (m, 7H), 3.33-3.44 (m, 2H), 3.63 (t,J=7.96 Hz, 1H), 3.79 (t, J=8.21 Hz, 1H), 3.90-4.01 (m, 3H), 4.34-4.50(m, 3H), 5.20 (d, J=4.55 Hz, 1H), 7.25 (dd, J=8.08, 2.27 Hz, 1H), 7.39(s, 1H), 7.44-7.49 (m, 1H), 7.50-7.57 (m, 2H), 7.82-7.90 (m, 2H), 8.26(d, J=8.59 Hz, 1H), 8.61 (s, 1H).

Step E: Preparation of1-Ethyl-3-((R)-3-((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 337)

A solution of tert-butyl((R)-8-((1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((R)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate(116 mg, 0.16 mmol) in TFA (0.5 mL, 6.529 mmol) and CH₂Cl₂ (1.50 mL) wasstirred at room temperature for 2 h then concentrated. The residue waspurified by prep-HPLC to give the title compound (74.3 mg, 70.3%). LCMSm/z=620.4 [M+H]⁺; ¹H NMR (400 MHz, D₂O) δ ppm 1.54 (t, J=7.20 Hz, 3H),1.66-1.76 (m, 1H), 1.78-1.93 (m, 4H), 2.39 (dd, J=13.39, 7.58 Hz, 1H),3.08-3.20 (m, 1H), 3.20-3.24 (m, 1H), 3.24 (s, 3H), 3.25-3.33 (m, 2H),3.40-3.49 (m, 2H), 3.87-4.02 (m, 2H), 4.09-4.15 (m, 1H), 4.16-4.25 (m,2H), 4.27-4.33 (m, 1H), 4.52 (q, J=7.24 Hz, 2H), 7.37 (dt, J=8.08, 1.26Hz, 1H), 7.51 (s, 1H), 7.54-7.64 (m, 2H), 7.67 (t, J=7.33 Hz, 1H),7.91-8.01 (m, 2H), 8.36 (d, J=8.08 Hz, 1H), 8.77 (s, 1H).

Example 1.68 Preparation of Additional Compounds of the PresentInvention

The following compounds were prepared using similar methods to the onesdescribed in the above examples from proper intermediate(s) obtainedthrough commercial sources or synthesized as describe above or accordingto literature preparation. The specific method(s) used to prepare thecompounds and the LCMS [M+H]⁺ for each compound are provided below:

Compound 2, Intermediates used: (R)-2-(chloromethyl)oxirane,3-(methylsulfonyl)phenol, naphthalene-2-sulfonyl chloride, Method C,LCMS m/z=575.4 [M+H]⁺; Compound 5, Intermediates used:3-(methylsulfonyl)phenol, 3-((2-hydroxyethyl)sulfonyl)phenol, Method C,LCMS m/z=605.4 [M+H]⁺; Compound 6, Intermediates used:8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C1,Method D, LCMS m/z=603.4 [M+H]⁺; Compound 7, Intermediates used:8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C2,Method D, LCMS m/z=615 [M+H]⁺; Compound 8, Intermediates used:8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C3,Method D, LCMS m/z=603.4 [M+H]⁺; Compound 9, Intermediates used:8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C4,Method D, LCMS m/z=657.4 [M+H]⁺; Compound 10, Intermediates used:8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C5,Method D, LCMS m/z=617.4 [M+H]⁺; Compound 11, Intermediates used:8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C6,Method D, LCMS m/z=631.6 [M+H]⁺; Compound 12, Intermediates used: benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,naphthalene-2-sulfonyl chloride, C7, Method C, LCMS m/z=600.4 [M+H]⁺;Compound 13, Intermediates used: benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,naphthalene-2-sulfonyl chloride, C8, Method C, LCMS m/z=629.4 [M+H]⁺;Compound 14, Intermediates used: benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,naphthalene-2-sulfonyl chloride, C9, Method C, LCMS m/z=671.4 [M+H]⁺;Compound 16, Intermediates used: tert-butyl(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-oxiran-2-ylmethyl)carbamate,C11, Method C, LCMS m/z=657.6 [M+H]⁺; Compound 17, Intermediates used:8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C12,Method D, LCMS m/z=651.6 [M+H]⁺; Compound 18, Intermediates used: benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,naphthalene-2-sulfonyl chloride, C62, Method C, LCMS m/z=615.4 [M+H]⁺;Compound 19, Intermediates used: benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,naphthalene-2-sulfonyl chloride, C14, Method C, LCMS m/z=629.6 [M+H]⁺;Compound 20, Intermediates used: benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,naphthalene-2-sulfonyl chloride, C15, Method C, LCMS m/z=651.2 [M+H]⁺;Compound 21, Intermediates used: benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,naphthalene-2-sulfonyl chloride, C16, Method C, LCMS m/z=616.2 [M+H]⁺;Compound 22, Intermediates used: benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,naphthalene-2-sulfonyl chloride, C17, Method C, LCMS m/z=604 [M+H]⁺;Compound 23, Intermediates used:(R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(R)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane, Method D, LCMSm/z=575.4 [M+H]⁺; Compound 24, Intermediates used:8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-iodophenoxy)methyl)oxirane, sodium oxetane-3-sulfinate,Methods B: Step D and I: Step B, LCMS m/z=617.4 [M+H]⁺; Compound 25,Intermediates used:8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C19,Method D, LCMS m/z=617.4 [M+H]⁺; Compound 26, Intermediates used:(S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C10,Method D, LCMS m/z=589.4 [M+H]⁺; Compound 27, Intermediates used:(R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C10,Method D, LCMS m/z=589.2 [M+H]⁺; Compound 29, Intermediates used:(2S)-1-(1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol,5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride, Method J, LCMSm/z=579.8 [M+H]⁺; Compound 30, Intermediates used:(2S)-1-(1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol,7-chlorobenzo[c][1,2,5]oxadiazole-4-sulfonyl chloride, Method J, LCMSm/z=601.4 [M+H]⁺; Compound 31, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3-chlorobenzene-1-sulfonyl chloride, Method E: (Step C, D), LCMS m/z=559[M+H]⁺; Compound 32, Intermediates used:(2S)-1-(1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol,4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride, MethodJ, LCMS m/z=556.4 [M+H]⁺; Compound 33, Intermediates used:(S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(R)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane, Method D, LCMSm/z=575.4 [M+H]⁺; Compound 34, Intermediates used:(S)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol, Method B: Step D,LCMS m/z=606.4 [M+H]⁺; Compound 35, Intermediates used:(R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol, Method B: Step D,LCMS m/z=605.6 [M+H]⁺; Compound 36, Intermediates used: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate, (1-ethyl-1H-pyrazol-4-yl)boronicacid, Method H: (Step C, E), LCMS m/z=619.4 [M+H]⁺; Compound 37,Intermediates used: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate,Method H: (Step C, E), LCMS m/z=591.2 [M+H]⁺; Compound 38, Intermediatesused: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,Method H: (Step C, E), LCMS m/z=633.6 [M+H]⁺; Compound 39, Intermediatesused: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,Method H: (Step C, E), LCMS m/z=631.4 [M+H]⁺; Compound 40, Intermediatesused: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,(1-methyl-1H-pyrazol-4-yl)boronic acid, Method H: (Step C, E), LCMSm/z=605.6 [M+H]⁺; Compound 41, Intermediates used: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method H:(Step C, E), LCMS m/z=630 [M+H]⁺; Compound 42, Intermediates used:tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,(4-sulfamoylphenyl)boronic acid, Method H: (Step C, E), LCMS m/z=680.4[M+H]⁺; Compound 43, Intermediates used: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,pyridin-4-ylboronic acid, Method H: (Step C, E), LCMS m/z=602.2 [M+H]⁺;Compound 44, Intermediates used: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,(2-methylpyridin-4-yl)boronic acid, Method H: Step, C, E, LCMS m/z=617.4[M+H]⁺; Compound 45, Intermediates used: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, Method H: (StepC, E), LCMS m/z=602.4 [M+H]⁺; Compound 46, Intermediates used:tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,pyridine-3-sulfonyl chloride, Method H: (Step B, E), LCMS m/z=526.6[M+H]⁺; Compound 47, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,benzenesulfonyl chloride, Method H: (Step B, E), LCMS m/z=525.6 [M+H]⁺;Compound 48, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3-methylbenzene-1-sulfonyl chloride, Method H: (Step B, E), LCMSm/z=539.4 [M+H]⁺; Compound 49, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3-methoxybenzene-1-sulfonyl chloride, Method H: (Step B, E), LCMSm/z=555.6 [M+H]⁺; Compound 50, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3-(trifluoromethyl)benzene-1-sulfonyl chloride, Method H: (Step B, E),LCMS m/z=593.4 [M+H]⁺; Compound 51, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,5-phenylthiophene-2-sulfonyl chloride, Method H: (Step B, E), LCMSm/z=607.6 [M+H]⁺; Compound 52, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3,5-dimethylisoxazole-4-sulfonyl chloride, Method H: (Step B, E), LCMSm/z=544.4 [M+H]⁺; Compound 53, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride, Method H:(Step B, E), LCMS m/z=596.4 [M+H]⁺; Compound 54, Intermediates used:tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3-fluorobenzene-1-sulfonyl chloride, Method H: (Step B, E), LCMSm/z=543.4 [M+H]⁺; Compound 55, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3-cyanobenzene-1-sulfonyl chloride, Method H: (Step B, E), LCMSm/z=550.4 [M+H]⁺; Compound 56, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,2-(2-aminothiazol-4-yl)acetic acid, Method K, LCMS m/z=525.6 [M+H]⁺;Compound 57, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,2-naphthoic acid, Method K, LCMS m/z=539.4 [M+H]⁺; Compound 58,Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,1-ethyl-5-methyl-1H-pyrazole-4-sulfonyl chloride, Method H: (Step B, E),LCMS m/z=557.4 [M+H]⁺; Compound 59, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,5-chloronaphthalene-2-sulfonyl chloride, Method H: (Step B, E), LCMSm/z=609.5 [M+H]⁺; Compound 60, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,benzofuran-2-sulfonyl chloride, Method H: (Step B, E), LCMS m/z=565.4[M+H]⁺; Compound 61, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,benzofuran-5-sulfonyl chloride, Method H: (Step B, E), LCMS m/z=565.4[M+H]⁺; Compound 62, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,1H-indole-5-sulfonyl chloride, Method H: (Step B, E), LCMS m/z=565.2[M+H]⁺; Compound 63, Intermediates used: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,pyridin-3-ylboronic acid, Method H: (Step C, E), LCMS m/z=602.4 [M+H]⁺;Compound 65, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,1H-indole-2-carboxylic acid, Method K, LCMS m/z=528.6 [M+H]⁺; Compound66, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,1H-indole-3-carboxylic acid, Method K, LCMS m/z=528.4 [M+H]⁺; Compound67, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,1H-indole-5-carboxylic acid, Method K, LCMS m/z=528.5 [M+H]⁺; Compound68, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,1H-indole-6-carboxylic acid, Method K, LCMS m/z=528.4 [M+H]⁺; Compound69, Intermediates used: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,Method H: Step E, LCMS m/z=603.2 [M+H]⁺; Compound 70, Intermediatesused: tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine, MethodH: (Step C, E), LCMS m/z=617.3 [M+H]⁺; Compound 71, Intermediates used:tert-butyl(8-((3-bromophenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)carbamate,pyrimidin-5-ylboronic acid, Method H: (Step C, E), LCMS m/z=603.4[M+H]⁺; Compound 72, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,pyridine-2-sulfonyl chloride, Method H: (Step B, E), LCMS m/z=526.6[M+H]⁺; Compound 73, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,6-chloronaphthalene-2-sulfonyl chloride, Method H: (Step B, E), LCMSm/z=609.6 [M+H]⁺; Compound 74, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,2,3-dihydrobenzofuran-5-sulfonyl chloride, Method H: (Step B, E), LCMSm/z=567.4 [M+H]⁺; Compound 75, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,quinoline-6-sulfonyl chloride, Method H: (Step B, E), LCMS m/z=576.2[M+H]⁺; Compound 76, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,C35, Method H: (Step B, E), LCMS m/z=565.4 [M+H]⁺; Compound 77,Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,1H-indazole-5-sulfonyl chloride, Method H: (Step B, E), LCMS m/z=565.5[M+H]⁺; Compound 79, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,ethanamine, Method H: Step D, E, LCMS m/z=658.4 [M+H]⁺; Compound 80,Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,propan-2-amine, Method H: Step D, E, LCMS m/z=672.4 [M+H]⁺; Compound 81,Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,2-methylpropan-1-amine, Method H: Step D, E, LCMS m/z=686.6 [M+H]⁺;Compound 82, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)(8-((4′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,2,2,2-trifluoroethanamine, Method H: Step D, E, LCMS m/z=712.4 [M+H]⁺;Compound 83, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,chroman-6-sulfonyl chloride, Method E, LCMS m/z=611.6 [M+H]⁺; Compound84, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonyl chloride, MethodE, LCMS m/z=626.4 [M+H]⁺; Compound 85, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,quinoline-3-sulfonyl chloride, Method H: (Step B, E), LCMS m/z=576.4[M+H]⁺; Compound 87, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,chroman-7-sulfonyl chloride, Method E, LCMS m/z=611.4 [M+H]⁺; Compound89, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,5-bromopyridine-3-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Methods A:(Step A, B, C) and M: (Step B, C, D), LCMS m/z=661.6 [M+H]⁺; Compound90, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,5-bromopyridine-3-sulfonyl chloride,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,Methods A: (Step A, B, C) and M: (Step B, C, D), LCMS m/z=636.7 [M+H]⁺;Compound 91, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,3-bromobenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method A:(Step A, B, C) and M: (Step B, C, D), LCMS m/z=660.7 [M+H]⁺; Compound92, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,quinoline-3-sulfonyl chloride, Method E, LCMS m/z=588.5 [M+H]⁺; Compound93, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,quinoline-6-sulfonyl chloride, Method E, LCMS m/z=606.8 [M+H]⁺; Compound94, Intermediates used: (R)-2-(chloromethyl)oxirane,3-((methylsulfonyl)methyl)phenol, Method C, LCMS m/z=589.4 [M+H]⁺;Compound 95, Intermediates used:(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C21,Method B: Step D, LCMS m/z=590.4 [M+H]⁺; Compound 96, Intermediatesused: (R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,3-bromobenzene-1-sulfonyl chloride, pyridin-4-ylboronic acid, Methods A:(Step A, B, C) and M: (Step B, C, D), LCMS m/z=632.6 [M+H]⁺; Compound97, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,3-bromobenzene-1-sulfonyl chloride, pyridin-3-ylboronic acid, Methods A:(Step A, B, C) and M: (Step B, C, D), LCMS m/z=632.6 [M+H]⁺; Compound98, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,quinoline-7-sulfonyl chloride, Method E, LCMS m/z=606.7 [M+H]⁺; Compound99, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,4-bromobenzene-1-sulfonyl chloride, pyridin-3-ylboronic acid, Methods A:(Step A, B, C) and M: (Step B, C, D), LCMS m/z=632.7 [M+H]⁺; Compound100, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,3-bromobenzene-1-sulfonyl chloride,2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, Methods A:(Step A, B, C) and M: (Step B, C, D), LCMS m/z=632.6 [M+H]⁺; Compound101, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,4-bromobenzene-1-sulfonyl chloride, pyridin-4-ylboronic acid, Methods A:(Step A, B, C) and M: (Step B, C, D), LCMS m/z=632.7 [M+H]⁺; Compound102, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,4-bromobenzene-1-sulfonyl chloride, diisopropyl pyridin-2-ylboronatecompound with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1:1), Methods A: (Step A, B, C) and M: (Step B, C, D), LCMS m/z=632.6[M+H]⁺; Compound 103, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,4-bromobenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Methods A:(Step A, B, C) and M: (Step B, C, D), LCMS m/z=660.8 [M+H]⁺; Compound104, Intermediates used:(R)-8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C21, Method B: Step D, LCMS m/z=611.6 [M+H]⁺; Compound 105,Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,isoquinoline-5-sulfonyl chloride, Method E, LCMS m/z=606.8 [M+H]⁺;Compound 106, Intermediates used:(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C22,Method B: Step D, LCMS m/z=634.8 [M+H]⁺; Compound 107, Intermediatesused: (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C23, Method B: Step D, LCMS m/z=646.2 [M+H]⁺; Compound 108,Intermediates used:(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C24,Method B: Step D, LCMS m/z=647.6 [M+H]⁺; Compound 109, Intermediatesused: (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C22, Method B: Step D, LCMS m/z=634.6 [M+H]⁺; Compound 110,Intermediates used:(R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C23,Method B: Step D, LCMS m/z=646.4 [M+H]⁺; Compound 111, Intermediatesused: (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane, Method B: Step D, LCMSm/z=576.6 [M+H]⁺; Compound 112, Intermediates used:(R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C10,Method B: Step D, LCMS m/z=590.2 [M+H]⁺; Compound 113, Intermediatesused: (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C3, Method B: Step D, LCMS m/z=604.6 [M+H]⁺; Compound 114, Intermediatesused: (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C13, Method B: Step D, LCMS m/z=616.4 [M+H]⁺; Compound 115,Intermediates used:(R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C1,Method B: Step D, LCMS m/z=604.4 [M+H]⁺; Compound 116, Intermediatesused: (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C5, Method B: Step D, LCMS m/z=618.4 [M+H]⁺; Compound 117, Intermediatesused: (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C2, Method B: Step D, LCMS m/z=616.2 [M+H]⁺; Compound 118, Intermediatesused: (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane, Method B: Step D, LCMSm/z=576.4 [M+H]⁺; Compound 119, Intermediates used:(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C3,Method B: Step D, LCMS m/z=604.4 [M+H]⁺; Compound 120, Intermediatesused: (S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,3-bromobenzene-1-sulfonyl chloride, (3-methylpyridin-2-yl)boronic acid,Methods A: (Step A, B, C) and M: (Step B, C, D), LCMS m/z=646.2 [M+H]⁺;Compound 121, Intermediates used:(R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C25,Method B: Step D, LCMS m/z=620.4 [M+H]⁺; Compound 122, Intermediatesused: (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C10, Method B: Step D, LCMS m/z=[M+H]⁺; Compound 124, Intermediatesused: (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C5, Method B: Step D, LCMS m/z=618.4 [M+H]⁺; Compound 125, Intermediatesused: (R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,3-bromobenzene-1-sulfonyl chloride,(6-(trifluoromethyl)pyridin-2-yl)boronic acid, Methods A: (Step A, B, C)and M: (Step B, C, D), LCMS m/z=700.6 [M+H]⁺; Compound 126,Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,3-bromobenzene-1-sulfonyl chloride, (3-fluoropyridin-2-yl)boronic acid,Methods A: (Step A, B, C) and M, LCMS m/z=650.6 [M+H]⁺; Compound 127,Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,3-bromobenzene-1-sulfonyl chloride, (5-methylpyridin-2-yl)boronic acid,Methods A: (Step A, B, C) and M: (Step B, C, D), LCMS m/z=646.2 [M+H]⁺;Compound 128, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,3-bromobenzene-1-sulfonyl chloride, (6-methylpyridin-2-yl)boronic acid,Methods A: (Step A, B, C) and M: (Step B, C, D), LCMS m/z=646.4 [M+H]⁺;Compound 129, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,3-bromobenzene-1-sulfonyl chloride, (4-methylpyridin-2-yl)boronic acid,Methods A: (Step A, B, C) and M: (Step B, C, D), LCMS m/z=646.4 [M+H]⁺;Compound 131, Intermediates used:(R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C26,Method B: Step D, LCMS m/z=606.6 [M+H]⁺; Compound 132, Intermediatesused: (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C27, Method B: Step D, LCMS m/z=634.6 [M+H]⁺; Compound 133,Intermediates used:(R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C28,Method B: Step D, LCMS m/z=633.6 [M+H]⁺; Compound 134, Intermediatesused: (R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,3-bromobenzene-1-sulfonyl chloride, (6-fluoropyridin-2-yl)boronic acid,Methods A: (Step A, B, C) and M: (Step B, C, D), LCMS m/z=650.6 [M+H]⁺;Compound 135, Intermediates used:(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C26,Method B: Step D, LCMS m/z=620.2 [M+H]⁺; Compound 136, Intermediatesused: (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,Method B: Step D, LCMS m/z=632.8 [M+H]⁺; Compound 137, Intermediatesused: (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)acetamide, Method B: StepD, LCMS m/z=619.4 [M+H]⁺; Compound 138, Intermediates used:(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C13,Method B: Step D, LCMS m/z=616.4 [M+H]⁺; Compound 139, Intermediatesused: (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C1, Method B: Step D, LCMS m/z=604.6 [M+H]⁺; Compound 140, Intermediatesused: (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C2, Method B: Step D, LCMS m/z=616.4 [M+H]⁺; Compound 141, Intermediatesused: (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C26, Method B: Step D, LCMS m/z=606.6 [M+H]⁺; Compound 142,Intermediates used:(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C28,Method B: Step D, LCMS m/z=633.6 [M+H]⁺; Compound 143, Intermediatesused: (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, Method B: Step D,LCMS m/z=602.6 [M+H]⁺; Compound 144, Intermediates used:(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, Method B: Step D,LCMS m/z=602.4 [M+H]⁺; Compound 145, Intermediates used:(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C29,Method B: Step D, LCMS m/z=676.6 [M+H]⁺; Compound 146, Intermediatesused: (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C30, Method B: Step D, LCMS m/z=632.4 [M+H]⁺; Compound 147,Intermediates used:(R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,Method B: Step D, LCMS m/z=632.4 [M+H]⁺; Compound 148, Intermediatesused: (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,Method B: Step D, LCMS m/z=642.4 [M+1-1]⁺; Compound 149, Intermediatesused: (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C27, Method B: Step D, LCMS m/z=634.6 [M+1-1]⁺; Compound 150,Intermediates used:(R)-8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C25, Method B: Step D, LCMS m/z=641.4 [M+H]⁺; Compound 151,Intermediates used:(R)-8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol, Method B: Step D,LCMS m/z=627.6 [M+H]⁺; Compound 152, Intermediates used:(R)-8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane, Method B: Step D, LCMSm/z=597.4 [M+H]⁺; Compound 153, Intermediates used:(R)-8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C3, Method B: Step D, LCMS m/z=625.4 [M+H]⁺; Compound 155, Intermediatesused:(R)-8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,Method B: Step D, LCMS m/z=653.6 [M+H]⁺; Compound 156, Intermediatesused:(R)-8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,Method B: Step D, LCMS m/z=663.4 [M+H]⁺; Compound 157, Intermediatesused: (R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromobenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=686.4 [M+H]⁺; Compound 158, Intermediates used:(R)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M,LCMS m/z=730.6 [M+H]⁺; Compound 159, Intermediates used:(R)-8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)acetamide, Method B: StepD, LCMS m/z=640.4 [M+H]⁺; Compound 161, Intermediates used:(S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,(R)-8-((5-bromo-2-ethoxyphenyl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-((((benzyloxy)carbonyl)amino)methyl)phenyl)boronic acid, Methods B:(Step A, B, C) and F: (Step A, B, E, F), LCMS m/z=740.4 [M+H]⁺; Compound162, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,5-bromo-2-fluorobenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=704.4 [M+H]⁺; Compound 164, Intermediates used:tert-butyl((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3-bromobenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=686.2 [M+H]⁺; Compound 166, Intermediates used:tert-butyl((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,5-bromo-2-isopropoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=714.6 [M+H]⁺; Compound 167, Intermediates used:tert-butyl((S)-2-hydroxy-3-(3-((1-(hydroxymethyl)cyclopropyl)sulfonyl)phenoxy)propyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=700.6 [M+H]⁺; Compound 168, Intermediates used:(S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=740.4 [M+H]⁺; Compound 169, Intermediates used:(R)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,5-bromo-2-fluorobenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=704.4 [M+H]⁺; Compound 170, Intermediates used: (R)-tert-butyl1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate, 3-bromobenzene-1-sulfonylchloride, (4-((((benzyloxy)carbonyl)amino)methyl)phenyl)boronic acid,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,Methods B: (Step A, B), M: (Step C, D), E: (Step A, B), and F: Step F,LCMS m/z=671.6 [M+H]⁺; Compound 171, Intermediates used: tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,5-bromo-2-isopropoxybezene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=714.8 [M+H]⁺; Compound 172, Intermediates used:(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,5-bromo-2-ethoxybezene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=756.6 [M+H]⁺; Compound 173, Intermediates used:(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,3-bromobenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=712.4 [M+H]⁺; Compound 174, Intermediates used:(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,3-bromobenzene-1-sulfonyl chloride,(4-(1-amino-2-methylpropan-2-yl)phenyl)boronic acid, Method F, LCMSm/z=772.6 [M+H]⁺; Compound 175, Intermediates used: (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,5-bromo-2-ethoxybezene-1-sulfonyl chloride,(4-(2-acetamidoethyl)phenyl)boronic acid, Method F, LCMS m/z=786.8[M+H]⁺; Compound 176, Intermediates used: (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,5-bromo-2-ethoxybezene-1-sulfonyl chloride,(4-(1-amino-2-methylpropan-2-yl)phenyl)boronic acid, Method F, LCMSm/z=772.6 [M+H]⁺; Compound 177, Intermediates used: (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,5-bromo-2-ethoxybezene-1-sulfonyl chloride,(4-(2-acetamidoethyl)phenyl)boronic acid, Method F, LCMS m/z=786.6[M+H]⁺; Compound 178, Intermediates used: tert-butyl((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=673.4 [M+H]⁺; Compound 179, Intermediates used:tert-butyl((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=717.6 [M+H]⁺; Compound 180, Intermediates used:(S)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromobenzene-1-sulfonyl chloride,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(4-(1-amino-2-methylpropan-2-yl)phenyl)boronic acid, Method B: (Step A,B, C) and F: (Step A, B, E, F), LCMS m/z=728.6 [M+H]⁺; Compound 181,Intermediates used: (R)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromobenzene-1-sulfonyl chloride,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(4-(1-amino-2-methylpropan-2-yl)phenyl)boronic acid, Method B: (Step A,B, C) and F: (Step A, B, E, F), LCMS m/z=728.6 [M+H]⁺; Compound 182,Intermediates used: (S)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromobenzene-1-sulfonyl chloride,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(4-(aminomethyl)-3-fluorophenyl)boronic acid, Method B: (Step A, B, C)and F: (Step A, B, E, F), LCMS m/z=704.6 [M+H]⁺; Compound 183,Intermediates used:(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)acetamide, Method B: StepD, LCMS m/z=620.2 [M+H]⁺; Compound 184, Intermediates used: (S)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromobenzene-1-sulfonyl chloride,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method B: (Step A, B, C) and F: (Step A, B, E, F), LCMS m/z=712.6[M+H]⁺; Compound 185, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromopyridine-3-sulfonyl chloride, Method E, LCMS m/z=662.6 [M+H]⁺;Compound 186, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromopyridine-3-sulfonyl chloride, Method E, LCMS m/z=660.6 [M+H]⁺;Compound 187, Intermediates used: (S)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(S)-2-methyl-24(3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)propan-1-ol,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method B:(Step A, B, C) and F: (Step A, B, E, F), LCMS m/z=732.8 [M+H]⁺; Compound188, Intermediates used: (S)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method B: (Step A, B, C) and F: (Step A, B, E, F), LCMS m/z=756.6[M+H]⁺; Compound 190, Intermediates used: (S)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromobenzene-1-sulfonyl chloride,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(4-(2-acetamidoethyl)phenyl)boronic acid, Method B: (Step A, B, C) andF: (Step A, B, E, F), LCMS m/z=742.6 [M+H]⁺; Compound 191, Intermediatesused: (R)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromobenzene-1-sulfonyl chloride,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(4-(2-acetamidoethyl)phenyl)boronic acid, Method B: (Step A, B, C) andF: (Step A, B, E, F), LCMS m/z=742.4 [M+H]⁺; Compound 192, Intermediatesused:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-2-methylbenzene-1-sulfonyl chloride, Method E, LCMS m/z=673.2[M+H]⁺; Compound 193, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-methoxybenzene-1-sulfonyl chloride, Method E, LCMS m/z=691.4[M+H]⁺; Compound 194, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,4-bromo-3-methylbenzene-1-sulfonyl chloride, Method E, LCMS m/z=675.4[M+H]⁺; Compound 195, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,pyridine-3-sulfonyl chloride, Method E, LCMS m/z=582.6 [M+H]⁺; Compound196, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,4-bromo-3-methylbenzene-1-sulfonyl chloride, Method E, LCMS m/z=675.4[M+H]⁺; Compound 197, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-2-methylbenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=700.6 [M+H]⁺; Compound 198, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-2-methylbenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=726.4 [M+H]⁺; Compound 200, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-2-methylbenzene-1-sulfonyl chloride, Method E, LCMS m/z=675.2[M+H]⁺; Compound 201, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-methoxybenzene-1-sulfonyl chloride, Method E, LCMS m/z=691.4[M+H]⁺; Compound 202, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,pyridine-3-sulfonyl chloride, Method E, LCMS m/z=582.4 [M+H]⁺; Compound203, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-2-methylbenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=700.4 [M+H]⁺; Compound 204, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-2-methylbenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=726.6 [M+H]⁺; Compound 205, Intermediates used:(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)acetamide, (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Methods E:(Step A, B) and M: (Step B, C, D), LCMS m/z=717.4 [M+H]⁺; Compound 206,Intermediates used:(S)-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)acetamide, (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-2-methoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Methods E:(Step A, B) and M: (Step B, C, D), LCMS m/z=703.2 [M+H]⁺; Compound 207,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=716.6 [M+H]⁺; Compound 208, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=716.8 [M+H]⁺; Compound 210, Intermediates used: (S)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromobenzene-1-sulfonyl chloride,(S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,(4-(aminomethyl)-3-fluorophenyl)boronic acid, Methods B: (Step A, B, C)and F: (Step A, B, E, F), LCMS m/z=710.4 [M+H]⁺; Compound 211,Intermediates used: (S)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromobenzene-1-sulfonyl chloride,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(4-(aminomethyl)-3-fluorophenyl)boronic acid, Methods B: (Step A, B, C)and F: (Step A, B, E, F), LCMS m/z=700.6 [M+H]⁺; Compound 212,Intermediates used: (R)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromobenzene-1-sulfonyl chloride,(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(4-(aminomethyl)-3-fluorophenyl)boronic acid, Methods B: (Step A, B, C)and F: (Step A, B, E, F), LCMS m/z=700.4 [M+H]⁺; Compound 213,Intermediates used: (R)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromobenzene-1-sulfonyl chloride,(S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,(4-(aminomethyl)-3-fluorophenyl)boronic acid, Methods B: (Step A, B, C)and F: (Step A, B, E, F), LCMS m/z=710.4 [M+H]⁺; Compound 214,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)boronic acid, Method F,LCMS m/z=744.8 [M+H]⁺; Compound 215, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)boronic acid, Method F,LCMS m/z=730.6 [M+H]⁺; Compound 216, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-fluorobenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=704.6 [M+H]⁺; Compound 217, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-fluorobenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=730.6 [M+H]⁺; Compound 218, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-fluorobenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=704.4 [M+H]⁺; Compound 219, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-fluorobenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=730.6 [M+H]⁺; Compound 220, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(aminomethyl)-3-fluorophenyl)boronic acid, Methods B: (Step A, B, C)and F: (Step A, B, E, F), LCMS m/z=748.6 [M+H]⁺; Compound 221,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-6-chloropyridine-3-sulfonyl chloride Method E, LCMS m/z=696.4[M+H]⁺; Compound 223, Intermediates used:(S)-2-methyl-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)propan-1-ol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Methods B:(Step A, B, C) and F: (Step A, B, E, F), LCMS m/z=718.6 [M+H]⁺; Compound224, Intermediates used:(S)-2-methyl-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)propan-1-ol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Methods B: (Step A, B, C) and F: (Step A, B, E, F), LCMS m/z=744.8[M+H]⁺; Compound 225, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=742.8 [M+H]⁺; Compound 226, Intermediates used: C10(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=688.6 [M+H]⁺; Compound 227, Intermediates used: tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=686.6 [M+H]⁺; Compound 228, Intermediates used:tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3-bromo-2-methoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=686.4 [M+H]⁺; Compound 229, Intermediates used:tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((S)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3-bromo-5-methoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=686.6 [M+H]⁺; Compound 230, Intermediates used:C26, (S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=704.4 [M+H]⁺; Compound 231, Intermediates used:(S)-2-((3-(methylsulfonyl)phenoxy)methyl)oxirane, (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=674.4 [M+H]⁺; Compound 232, Intermediates used: C3, (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method M:(Step B, C, D), LCMS m/z=702.4 [M+H]⁺; Compound 233, Intermediates used:C33, (R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,Method B: Step D, LCMS m/z=608.6 [M+H]⁺; Compound 234, Intermediatesused: C33,(R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, MethodB: Step D, LCMS m/z=608.6 [M+H]⁺; Compound 235, Intermediates used: C33(R)-8-((1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)sulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,Method B: Step D, LCMS m/z=629.4 [M+H]⁺; Compound 236, Intermediatesused:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,4-methyl-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride, Method E, LCMSm/z=662.6 [M+H]⁺; Compound 237, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-ethoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Method F,LCMS m/z=730.6 [M+H]⁺; Compound 238, Intermediates used:(S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid, Methods B:(Step A, B, C) and F: (Step A, B, E, F), LCMS m/z=726.4 [M+H]⁺; Compound239, Intermediates used:(S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Methods B: (Step A, B, C) and F: (Step A, B, E, F), LCMS m/z=752.2[M+H]⁺; Compound 240, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,2-methylpropan-2-amine, Methods B and L, LCMS m/z=742.8 [M+H]⁺; Compound241, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,2-methylbutan-2-amine, Methods B and L, LCMS m/z=756.6 [M+H]⁺; Compound242, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,2,2,2-trifluoroethanamine, Methods B and L, LCMS m/z=768.6 [M+H]⁺;Compound 243, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,azetidine, Methods B and L, LCMS m/z=726.2 [M+H]⁺; Compound 244,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,propan-1-amine, Methods B and L, LCMS m/z=728.6 [M+H]⁺; Compound 245,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,butan-1-amine, Methods B and L, LCMS m/z=742.8 [M+H]⁺; Compound 246,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,morpholine, Methods B and L, LCMS m/z=756.6 [M+H]⁺; Compound 247,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,2-methoxyethanamine, Methods B and L, LCMS m/z=744.6 [M+H]⁺; Compound248, Intermediates used:(R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C34,Method B: Step D, LCMS m/z=624.4 [M+H]⁺; Compound 249, Intermediatesused: (R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine,C34, Method B: Step D, LCMS m/z=624.4 [M+H]⁺; Compound 250,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C36,Method E, LCMS m/z=667.2 [M+H]⁺; Compound 251, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)phenyl)boronic acid,Method F, LCMS m/z=758.4 [M+H]⁺; Compound 252, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=726.4 [M+H]⁺; Compound 253, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=712.6 [M+H]⁺; Compound 254, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=726.4 [M+H]⁺; Compound 255, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=712.6 [M+H]⁺; Compound 256, Intermediates used: C10,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=714.6 [M+H]⁺; Compound 257, Intermediates used: C10,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,5-bromo-2-ethoxybenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=714.6 [M+H]⁺; Compound 258, Intermediates used: C10,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=700.4 [M+H]⁺; Compound 259, Intermediates used:tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,C37, Method E, LCMS m/z=637.6 [M+H]⁺; Compound 260, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C36,Method E, LCMS m/z=667.4 [M+H]⁺; Compound 261, Intermediates used: C10,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-bromo-4-methoxybenzene-1-sulfonyl chloride,(4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid,Method F, LCMS m/z=700.6 [M+H]⁺; Compound 262, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,2-methylpropan-2-amine, Methods B and L, LCMS m/z=742.8 [M+H]⁺; Compound263, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,2-methylbutan-2-amine, Methods B and L, LCMS m/z=756.6 [M+H]⁺; Compound264, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,2,2,2-trifluoroethanamine, Methods B and L, LCMS m/z=768.6 [M+H]⁺;Compound 265, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,azetidine, Methods B and L, LCMS m/z=726.4 [M+H]⁺; Compound 266,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,morpholine, Methods B and L, LCMS m/z=756.6 [M+H]⁺; Compound 267,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,2-methoxyethanamine, Methods B and L, LCMS m/z=744.8 [M+H]⁺; Compound268, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,ethanamine, Methods B and L, LCMS m/z=714.6 [M+H]⁺; Compound 269,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,cyclobutanamine, Methods B and L, LCMS m/z=740.6 [M+H]⁺; Compound 270,Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,tert-butyl (2-aminoethyl)carbamate, Methods B and L, LCMS m/z=729.6[M+H]⁺; Compound 271, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,tert-butyl (3-aminopropyl)carbamate, Methods B and L, LCMS m/z=743.8[M+H]⁺; Compound 272, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-tert-butyl 1-oxa-8-azaspiro[4.5]decan-3-ylcarbamate,3-bromobenzene-1-sulfonyl chloride, (4-formylphenyl)boronic acid,2-methylpropan-1-amine, Methods B and L, LCMS m/z=742.6 [M+H]⁺; Compound273, Intermediates used: tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,C38, Method E, LCMS m/z=651.6 [M+H]⁺; Compound 274, Intermediates used:tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,C48, Method E, LCMS m/z=637.6 [M+H]⁺; Compound 275, Intermediates used:tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,C36, Method E, LCMS m/z=637.6 [M+H]⁺; Compound 276, Intermediates used:tert-butyl((S)-3-(3-((2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,C36, Method E2, LCMS m/z=654.6 [M+H]⁺; Compound 277, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (S)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C48, Method E, LCMSm/z=637.6 [M+H]⁺; Compound 278, Intermediates used: tert-butyl((S)-3-(34(2-amino-2-oxoethyl)sulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,C48, Method E2, LCMS m/z=654.6 [M+H]⁺; Compound 280, Intermediates used:tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-sulfonyl chloride, MethodN, LCMS m/z=607.6 [M+H]⁺; Compound 281, Intermediates used: tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-sulfonyl chloride, MethodN, LCMS m/z=608.4 [M+H]⁺; Compound 282, Intermediates used: tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,5,6,7,8-tetrahydroquinoline-3-sulfonyl chloride, Method N, LCMSm/z=606.6 [M+H]⁺; Compound 283, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C48,Method E, LCMS m/z=667.2 [M+H]⁺; Compound 284, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C43,Method E, LCMS m/z=638.6 [M+1-1]⁺; Compound 285, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C44,Method E, LCMS m/z=640.2 [M+H]⁺; Compound 286, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C45,Method E, LCMS m/z=653.4 [M+H]⁺; Compound 287, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,3-methyl-3H-imidazo[4,5-b]pyridine-5-sulfonyl chloride, Method E, LCMSm/z=636.6 [M+H]⁺; Compound 288, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C46,Method E, LCMS m/z=681.4 [M+H]⁺; Compound 289, Intermediates used:tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-7-sulfonyl chloride, Method N,LCMS m/z=610.6 [M+H]⁺; Compound 290, Intermediates used: tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-sulfonyl chloride,Method N, LCMS m/z=623.6 [M+H]⁺; Compound 291, Intermediates used:tert-butyl ((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,3,4-dihydro-2H-pyrano[2,3-b]pyridine-6-sulfonyl chloride, Method N, LCMSm/z=608.8 [M+H]⁺; Compound 292, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride, Method E, LCMSm/z=676.4 [M+H]⁺; Compound 293, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride, Method E, LCMSm/z=676.4 [M+H]⁺; Compound 294, Intermediates used:(S)-2-methyl-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)propan-1-ol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride, Method E, LCMSm/z=678.4 [M+H]⁺; Compound 295, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C63,Method E, LCMS m/z=662.6 [M+H]⁺; Compound 296, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(S)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C63,Method E, LCMS m/z=662.6 [M+H]⁺; Compound 298, Intermediates used:(S)-2,2-difluoro-2-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)ethanol,(R)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride, Method B, LCMSm/z=686.4 [M+H]⁺; Compound 299, Intermediates used: C33, (R)-benzyl3-((tert-butoxycarbonyl)amino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride, Method B, LCMSm/z=652.6 [M+H]⁺; Compound 300, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,naphthalene-2-sulfonyl chloride, Method E, LCMS m/z=631.6 [M+H]⁺;Compound 301, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C56,Method E, LCMS m/z=675.4 [M+H]⁺; Compound 302, Intermediates used:(S)-(1-((3-(oxiran-2-ylmethoxy)phenyl)sulfonyl)cyclopropyl)methanol,(R)-benzyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C57,Method E, LCMS m/z=621.6 [M+H]⁺; Compound 303, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C47, Method E, LCMSm/z=609.6 [M+H]⁺; Compound 304, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonylchloride, Method E, LCMS m/z=667.4 [M+H]⁺; Compound 305, Intermediatesused: (S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C42, Method E, LCMSm/z=637.6 [M+H]⁺; Compound 306, Intermediates used: C26, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,1-ethyl-4-oxo-1,4-dihydroquinoline-3-sulfonyl chloride, Method E, LCMSm/z=650.6 [M+H]⁺; Compound 307, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C49, Method E, LCMSm/z=591.4 [M+H]⁺; Compound 308, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, 1H-indole-3-sulfonylchloride, Method E, LCMS m/z=590.6 [M+1⁻¹]⁺; Compound 309, Intermediatesused: (S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C31, Method E, LCMSm/z=591.4 [M+H]⁺; Compound 311, Intermediates used: tert-butyl((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,1H-indole-3-sulfonyl chloride, Method A: Step F, G, LCMS m/z=564.4[M+H]⁺; Compound 312, Intermediates used: C26, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, 1H-indole-3-sulfonylchloride, Method E, LCMS m/z=594.6 [M+H]⁺; Compound 313, Intermediatesused: (S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C50, Method E, LCMSm/z=607.6 [M+H]⁺; Compound 314, Intermediates used: tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate, C61, bromoethane, MethodG, LCMS m/z=664.6 [M+H]⁺; Compound 315, Intermediates used: tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,C53, iodoethane, Method G, LCMS m/z=660.6 [M+H]⁺; Compound 316,Intermediates used: tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,7-fluoro-4-hydroxyquinoline-3-sulfonyl chlorideiodoethane, Method G,LCMS m/z=664.6 [M+H]⁺; Compound 317, Intermediates used: tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,C60, iodoethane, Method G, LCMS m/z=660.6 [M+H]⁺; Compound 318,Intermediates used: tert-butyl((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropyl)((R)-1-oxa-8-azaspiro[4.5]decan-3-yl)carbamate,4-hydroxy-7-methylquinoline-3-sulfonyl chloride, iodoethane, Method G,LCMS m/z=660.6 [M+H]⁺; Compound 319, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C51, Method E, LCMSm/z=592.4 [M+H]⁺; Compound 323, Intermediates used: C3, C52, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, Method E3, LCMSm/z=638.6 [M+H]⁺; Compound 324, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C60, Method E3, LCMSm/z=632.6 [M+H]⁺; Compound 325, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C61, Method E3, LCMSm/z=636.6 [M+H]⁺; Compound 328, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, C52, Method E3, LCMSm/z=636.6 [M+H]⁺; Compound 330, Intermediates used:(S)-2-((3-(cyclopropylsulfonyl)phenoxy)methyl)oxirane, (R)-benzyl3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate,4-hydroxy-7-methylquinoline-3-sulfonyl chloride, Method E3, LCMSm/z=632.6 [M+H]⁺; Compound 335, Intermediates used:

naphthalene-2-sulfonyl chloride, 3-((methylsulfonyl)methyl)phenol,Method C, LCMS m/z=589.2 [M+H]⁺; and Compound 336, Intermediates used:(R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-amine, C21,Method B: Step D, LCMS m/z=590.4 [M+H]⁺.

The following NMR data are for selected compounds from above:

Compound 2, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37 (s, 9H), 1.47-1.81 (m,5H), 1.84-2.01 (m, 1H), 2.42-2.48 (m, 1H), 2.57-2.76 (m, 3H), 2.92-3.01(m, 1H), 3.27-3.39 (m, 3H), 3.43-3.50 (m, 1H), 3.51-3.59 (m, 1H),3.63-3.74 (m, 1H), 4.32-4.54 (m, 1H), 7.66-7.80 (m, 3H), 8.08 (d, J=7.9Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.43 (s, 1H).

Compound 6, ¹H NMR (400 MHz, CD₃OD) δ ppm 0.98 (t, J=7.33 Hz, 3H),1.59-1.72 (m, 3H), 1.76-1.95 (m, 4H), 2.28 (dd, J=12.63, 7.33 Hz, 1H),2.71-2.89 (m, 2H), 3.06-3.19 (m, 3H), 3.26 (t, J=9.98 Hz, 1H), 3.42-3.55(m, 2H), 3.79-3.89 (m, 1H), 3.92-4.02 (m, 2H), 4.03-4.12 (m, 2H), 4.23(d, J=4.80 Hz, 1H), 7.29 (d, J=7.83 Hz, 1H), 7.44 (s, 1H), 7.48-7.60 (m,2H), 7.62-7.74 (m, 2H), 7.77 (d, J=8.59 Hz, 1H), 8.01 (d, J=7.83 Hz,1H), 8.08 (d, J=6.57 Hz, 2H), 8.37 (s, 1H).

Compound 7, ¹H NMR (400 MHz, CD₃OD) δ ppm 0.09-0.17 (m, 2H), 0.46-0.55(m, 2H), 0.86-0.99 (m, 1H), 1.60-1.71 (m, 1H), 1.75-1.94 (m, 4H), 2.28(dd, J=13.77, 7.96 Hz, 1H), 2.73-2.90 (m, 2H), 3.06-3.18 (m, 3H),3.22-3.30 (m, 1H), 3.49 (t, J=11.49 Hz, 2H), 3.78-3.88 (m, 1H),3.92-4.03 (m, 2H), 4.08 (d, J=4.29 Hz, 2H), 4.22 (dd, J=8.46, 3.41 Hz,1H), 7.30 (t, J=3.16 Hz, 1H), 7.46 (s, 1H), 7.51-7.57 (m, 2H), 7.61-7.74(m, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8.08(d, J=7.33 Hz, 2H), 8.38 (s, 1H).

Compound 8, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.23 (d, J=6.57 Hz, 6H), 1.66(m, 1H), 1.75-1.95 (m, 4H), 2.28 (dd, J=12.76, 7.71 Hz, 1H), 2.72-2.90(m, 2H), 3.05-3.18 (m, 1H), 3.21-3.29 (m, 1H), 3.34 (m, 1H), 3.48 (t,J=12.38 Hz, 2H), 3.78-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.08 (d, J=4.80Hz, 2H), 4.23 (dd, J=8.97, 3.66 Hz, 1H), 7.30 (d, J=7.58 Hz, 1H), 7.40(s, 1H), 7.45-7.50 (m, 1H), 7.56 (t, J=7.96 Hz, 1H), 7.61-7.73 (m, 2H),7.77 (d, J=8.59 Hz, 1H), 8.00 (d, J=8.08 Hz, 1H), 8.07 (d, J=8.34 Hz,2H), 8.37 (s, 1H).

Compound 9, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.67 (td, J=10.74, 4.17 Hz,1H), 1.76-1.92 (m, 4H), 2.28 (ddd, J=13.58, 8.15, 2.53 Hz, 1H),2.49-2.64 (m, 2H), 2.73-2.90 (m, 2H), 3.12 (dt, J=12.82, 9.51 Hz, 1H),3.22-3.30 (m, 1H), 3.42-3.54 (m, 4H), 3.80-3.88 (m, 1H), 3.92-4.03 (m,2H), 4.10 (d, J=4.80 Hz, 2H), 4.19-4.27 (m, 1H), 7.33 (ddd, J=7.39,2.34, 2.15 Hz, 1H), 7.50 (d, J=2.02 Hz, 1H), 7.53-7.62 (m, 2H),7.63-7.73 (m, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.00 (d, J=7.83 Hz,1H), 8.08 (d, J=8.59 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 11, ¹H NMR (400 MHz, CD₃OD) δ ppm 0.86 (dd, J=6.57, 1.01 Hz,6H), 1.46-1.55 (m, 2H), 1.56-1.70 (m, 2H), 1.76-1.92 (m, 4H), 2.28 (ddd,J=13.64, 8.08, 2.53 Hz, 1H), 2.73-2.89 (m, 2H), 3.07-3.15 (m, 1H),3.15-3.22 (m, 2H), 3.25 (dt, J=12.82, 2.81 Hz, 1H), 3.49 (t, J=12.76 Hz,2H), 3.80-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4.12 (m, 2H), 4.19-4.27(m, 1H), 7.29 (ddd, J=8.08, 2.53, 1.26 Hz, 1H), 7.42-7.48 (m, 1H), 7.54(ddd, J=15.28, 7.83, 7.71 Hz, 2H), 7.63-7.73 (m, 2H), 7.77 (dd, J=8.59,1.77 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.08 (d, J=8.84 Hz, 2H), 8.38 (d,J=1.52 Hz, 1H).

Compound 12, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.59-1.70 (m, 1H), 1.71-1.93(m, 4H), 2.14-2.32 (m, 1H), 2.32-2.53 (m, 1H), 2.73-2.88 (m, 2H),2.88-3.03 (m, 1H), 3.08-3.26 (m, 1H), 3.33-3.42 (m, 1H), 3.43-3.55 (m,2H), 3.75-3.85 (m, 1H), 3.87-4.04 (m, 2H), 7.14-7.57 (m, 4H), 7.63-7.73(m, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.08(d, J=8.59 Hz, 2H), 8.38 (s, 1H).

Compound 13, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61-1.74 (m, 1H), 1.74-1.95(m, 8H), 1.96-2.06 (m, 2H), 2.29 (dd, J=13.64, 8.08 Hz, 1H), 2.56-2.68(m, 1H), 2.74-2.89 (m, 2H), 3.07-3.18 (m, 1H), 3.25 (dd, J=12.88, 3.03Hz, 1H), 3.43-3.54 (m, 2H), 3.79-3.88 (m, 1H), 3.93-4.02 (m, 2H), 4.08(dd, J=4.93, 2.40 Hz, 2H), 4.18-4.27 (m, 1H), 7.29 (ddd, J=8.08, 2.53,1.01 Hz, 1H), 7.42 (t, J=2.52 Hz, 1H), 7.47-7.51 (m, 1H), 7.54 (t,J=8.08 Hz, 1H), 7.68 (qd, J=7.96, 7.71 Hz, 2H), 7.77 (dd, J=8.59, 1.77Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.08 (d, J=8.84 Hz, 2H), 8.38 (d,J=1.26 Hz, 1H).

Compound 14, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.68 (td, J=10.99, 4.17 Hz,1H), 1.76-1.95 (m, 6H), 2.23-2.38 (m, 3H), 2.74-2.89 (m, 2H), 3.07-3.17(m, 1H), 3.21-3.30 (m, 2H), 3.49 (t, J=12.88 Hz, 2H), 3.79-3.88 (m, 1H),3.92-4.02 (m, 2H), 4.04-4.12 (m, 2H), 4.19-4.27 (m, 1H), 7.32 (ddd,J=8.08, 2.53, 1.26 Hz, 1H), 7.46 (t, J=2.27 Hz, 1H), 7.56 (dt, J=15.66,7.83 Hz, 2H), 7.68 (qd, J=8.25, 8.08 Hz, 2H), 7.77 (dd, J=8.72, 1.89 Hz,1H), 8.01 (d, J=8.08 Hz, 1H), 8.08 (d, J=8.59 Hz, 2H), 8.38 (d, J=1.52Hz, 1H).

Compound 16, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.08 (q, J=12.29 Hz, 2H),1.14-1.31 (m, 3H), 1.57-1.72 (m, 4H), 1.75-1.93 (m, 7H), 2.29 (ddd,J=13.77, 7.96, 2.02 Hz, 1H), 2.73-2.90 (m, 2H), 3.09 (dd, J=5.94, 1.89Hz, 2H), 3.14 (t, J=9.22 Hz, 1H), 3.22-3.30 (m, 1H), 3.42-3.57 (m, 2H),3.78-3.88 (m, 1H), 3.93-4.02 (m, 2H), 4.04-4.12 (m, 2H), 4.18-4.27 (m,1H), 7.29 (ddd, J=7.89, 2.59, 1.39 Hz, 1H), 7.45 (t, J=2.27 Hz, 1H),7.49-7.53 (m, 1H), 7.55 (t, J=7.56 Hz, 1H), 7.63-7.73 (m, 2H), 7.77 (dd,J=8.72, 1.89 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.09 (d, J=8.84 Hz, 2H),8.38 (d, J=1.52 Hz, 1H).

Compound 17, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.16 (dddd, J=11.81, 7.83,7.64, 3.79 Hz, 1H), 1.52-1.70 (m, 2H), 1.77-1.95 (m, 5H), 2.28 (ddd,J=13.64, 8.21, 2.40 Hz, 1H), 2.73-2.89 (m, 2H), 3.12 (dt, J=12.82, 9.51Hz, 1H), 3.21-3.29 (m, 1H), 3.33-3.43 (m, 2H), 3.49 (t, J=12.63 Hz, 2H),3.79-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4.13 (m, 2H), 4.19-4.27 (m,1H), 7.32 (dt, J=7.33, 2.27 Hz, 1H), 7.47 (d, J=2.02 Hz, 1H), 7.52-7.60(m, 2H), 7.68 (qd, J=8.25, 8.08 Hz, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H),8.01 (d, J=8.08 Hz, 1H), 8.08 (d, J=8.59 Hz, 2H), 8.38 (d, J=1.26 Hz,1H).

Compound 18, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.68 (td, J=10.99, 4.17 Hz,1H), 1.76-2.08 (m, 6H), 2.11-2.22 (m, 2H), 2.29 (ddd, J=13.77, 8.08,2.15 Hz, 1H), 2.40-2.53 (m, 2H), 2.73-2.89 (m, 2H), 3.06-3.17 (m, 1H),3.26 (ddd, J=12.82, 9.66, 3.03 Hz, 1H), 3.44-3.56 (m, 2H), 3.79-3.88 (m,1H), 3.92-4.03 (m, 3H), 4.03-4.11 (m, 2H), 4.17-4.27 (m, 1H), 7.28 (dd,J=6.57, 1.77 Hz, 1H), 7.40 (t, J=2.77 Hz, 1H), 7.47 (ddd, J=7.71, 1.26,1.14 Hz, 1H), 7.54 (t, J=7.96 Hz, 1H), 7.63-7.73 (m, 2H), 7.77 (dd,J=8.72, 1.89 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.09 (d, J=8.59 Hz, 2H),8.38 (d, J=1.52 Hz, 1H).

Compound 19, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.56-1.76 (m, 5H), 1.76-1.92(m, 6H), 1.92-2.03 (m, 2H), 2.28 (ddd, J=13.58, 8.15, 2.27 Hz, 1H),2.74-2.89 (m, 2H), 3.07-3.17 (m, 1H), 3.22-3.29 (m, 1H), 3.43-3.56 (m,2H), 3.67 (dq, J=8.65, 7.14 Hz, 1H), 3.80-3.88 (m, 1H), 3.92-4.02 (m,2H), 4.04-4.12 (m, 2H), 4.22 (sxt, J=3.79 Hz, 1H) 7.29 (ddd, J=8.02,2.59, 1.01 Hz, 1H), 7.44 (t, J=2.53 Hz, 1H), 7.53 (ddd, J=16.42, 8.08,7.83 Hz, 2H), 7.63-7.74 (m, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.01(d, J=7.83 Hz, 1H), 8.08 (d, J=8.84 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 20, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.66 (dd, J=10.86, 4.29 Hz,1H), 1.75-1.92 (m, 4H), 2.28 (ddd, J=13.83, 8.15, 1.77 Hz, 1H),2.74-2.89 (m, 2H), 3.02-3.12 (m, 1H), 3.22 (ddd, J=12.69, 9.54, 3.03 Hz,1H), 3.45-3.56 (m, 2H), 3.82 (td, J=8.97, 3.03 Hz, 1H), 3.90-4.02 (m,4H), 4.17 (td, J=9.09, 5.56 Hz, 1H), 4.48 (d, J=1.26 Hz, 2H), 7.09-7.15(m, 3H), 7.24 (t, J=7.45 Hz, 3H), 7.27-7.33 (m, 2H), 7.45 (t, J=8.08 Hz,1H), 7.63-7.74 (m, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=7.83Hz, 1H), 8.09 (d, J=8.84 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 21, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.68 (td, J=10.74, 3.92 Hz,1H), 1.75-1.92 (m, 4H), 2.24-2.34 (m, 1H), 2.73-2.88 (m, 2H), 3.06-3.16(m, 1H), 3.21-3.29 (m, 1H), 3.44-3.56 (m, 2H), 3.84 (dd, J=8.21, 6.19Hz, 1H) 3.93-4.03 (m, 2H), 4.09 (d, J=5.05 Hz, 2H), 4.23 (dd, J=8.72,3.92 Hz, 1H), 4.37 (d, J=7.58 Hz, 4H), 4.53 (q, J=7.24 Hz, 1H), 7.37 (d,J=7.07 Hz, 1H), 7.49 (s, 1H), 7.59 (dt, J=15.16, 7.58 Hz, 2H), 7.64-7.74(m, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.09(d, J=8.84 Hz, 2H), 8.38 (s, 1H).

Compound 22, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.68 (td, J=11.12, 4.29 Hz,1H), 1.76-1.93 (m, 4H), 2.25-2.33 (m, 1H), 2.73-2.87 (m, 2H), 3.08-3.17(m, 1H), 3.22-3.28 (m, 1H), 3.35-3.43 (m, 3H), 3.46-3.53 (m, 3H), 3.58(td, J=6.76, 1.64 Hz, 2H), 3.79-3.88 (m, 1H), 3.94-4.02 (m, 2H), 4.10(d, J=5.05 Hz, 2H), 4.19-4.27 (m, 1H), 7.37 (d, J=9.35 Hz, 1H), 7.52 (d,J=1.77 Hz, 1H), 7.58-7.64 (m, 2H), 7.64-7.74 (m, 2H), 7.77 (dd, J=8.59,1.77 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8.09 (d, J=9.09 Hz, 2H), 8.38 (d,J=1.01 Hz, 1H).

Compound 23, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.67 (td, J=10.74, 4.17 Hz,1H), 1.76-1.92 (m, 4H), 2.28 (dd, J=13.89, 8.34 Hz, 1H), 2.72-2.89 (m,2H), 3.05-3.14 (m, 4H), 3.28 (dd, J=12.76, 3.16 Hz, 1H), 3.43-3.55 (m,2H), 3.77-3.88 (m, 1H), 3.92-4.02 (m, 2H), 4.08 (dd, J=4.93, 1.64 Hz,2H), 4.23 (dddd, J=9.60, 4.99, 4.86, 3.03 Hz, 1H), 7.28 (dd, J=6.57,2.78 Hz, 1H), 7.49 (d, J=1.52 Hz, 1H), 7.52-7.58 (m, 2H), 7.62-7.73 (m,2H), 7.77 (dd, J=8.59, 2.02 Hz, 1H), 8.00 (d, J=8.08 Hz, 1H), 8.08 (d,J=9.09 Hz, 2H), 8.37 (d, J=1.26 Hz, 1H).

Compound 24, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.68 (td, J=10.86, 4.29 Hz,1H), 1.76-1.95 (m, 4H), 2.28 (ddd, J=13.71, 8.15, 2.40 Hz, 1H),2.74-2.90 (m, 2H), 3.12 (dt, J=12.63, 9.60 Hz, 1H), 3.26 (ddd, J=12.88,9.98, 3.16 Hz, 1H), 3.49 (t, J=12.51 Hz, 2H), 3.79-3.88 (m, 1H),3.92-4.02 (m, 2H), 4.08 (d, J=5.05 Hz, 2H), 4.19-4.26 (m, 1H), 4.66-4.75(m, 1H), 4.76-4.89 (m, 4H), 7.32 (ddd, J=8.08, 2.65, 1.14 Hz, 1H), 7.46(t, J=2.27 Hz, 1H), 7.51 (dt, J=8, 1.26 Hz, 1H), 7.56 (t, J=2.83 Hz,1H), 7.68 (qd, J=8.25, 8.08 Hz, 2H), 7.77 (dd, J=8.59, 1.77 Hz, 1H),8.01 (d, J=8.08 Hz, 1H), 8.08 (d, J=8.59 Hz, 2H), 8.38 (d, J=1.26 Hz,1H).

Compound 25, ¹H NMR (400 MHz, CD₃OD) δ ppm 0.97 (t, J=7.45 Hz, 3H), 1.22(d, J=6.82 Hz, 3H), 1.35-1.48 (m, 1H), 1.67 (td, J=10.86, 3.79 Hz, 1H),1.76-1.98 (m, 5H), 2.22-2.33 (m, 1H), 2.72-2.89 (m, 2H), 3.12 (ddd,J=12.51, 9.60, 9.47 Hz, 2H), 3.22-3.29 (m, 1H), 3.49 (t, J=12.76 Hz,1H), 3.78-3.89 (m, 1H), 3.92-4.02 (m, 2H), 4.08 (d, J=4.29 Hz, 2H),4.18-4.27 (m, 1H), 7.30 (dd, J=8.21, 1.64 Hz, 1H), 7.41 (s, 1H), 7.47(d, J=8.21 Hz, 1H), 7.55 (t, J=7.96 Hz, 1H), 7.63-7.73 (m, 2H), 7.77(dd, J=8.59, 1.52 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.08 (d, J=8.84 Hz,2H), 8.37 (s, 1H).

Compound 26, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.20 (t, J=7.33 Hz, 3H), 1.68(dt, J=10.99, 4.42 Hz, 1H), 1.75-1.97 (m, 4H), 2.28 (dd, J=13.77, 8.21Hz, 1H), 2.73-2.89 (m, 2H), 3.06-3.15 (m, 1H), 3.20 (q, J=7.33 Hz, 2H),3.24-3.29 (m, 2H), 3.34-3.37 (m, 1H), 3.44-3.56 (m, 2H), 3.79-3.85 (m,1H), 3.92-4.02 (m, 2H), 4.08 (dd, J=5.05, 1.52 Hz, 2H), 4.18-4.26 (m,1H), 7.30 (ddd, J=8.08, 2.53, 1.01 Hz, 1H), 7.44 (t, J=J=2.27 Hz, 1H),7.50 (dt, J=8.21, 1.39 Hz, 1H), 7.55 (t, J=8.08 Hz, 1H), 7.64-7.74 (m,2H), 7.78 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=8.08 Hz, 1H), 8.09 (d,J=8.84 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 27, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.20 (t, J=7.45 Hz, 3H), 1.68(td, J=10.99, 4.17 Hz, 1H), 1.75-1.97 (m, 4H), 2.29 (dd, J=13.64, 8.08Hz, 1H), 2.81 (dq, J=14.43, 11.27 Hz, 2H), 3.07-3.16 (m, 1H), 3.16-3.28(m, 3H), 3.44-3.54 (m, 2H), 3.56-3.77 (m, 1H), 3.80-3.88 (m, 1H),3.91-4.02 (m, 2H), 4.08 (dd, J=5.18, 1.64 Hz, 2H), 4.17-4.26 (m, 1H),7.30 (ddd, J=8.08, 2.65, 1.14 Hz, 1H), 7.44 (t, J=2.53 Hz, 1H), 7.50(dt, J=8.08, 1.39 Hz, 1H), 7.56 (t, J=7.83 Hz, 1H), 7.63-7.74 (m, 2H),7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d, J=7.83 Hz, 1H), 8.06-8.11 (m,2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 29, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.60-1.69 (m, 1H), 1.77-1.91(m, 8H), 2.31 (ddd, J=13.71, 8.27, 2.27 Hz, 1H), 2.63-2.77 (m, 2H), 2.85(bs, 4H), 3.11 (s, 3H), 3.12-3.19 (m, 1H), 3.25-3.30 (m, 1H), 3.33-3.44(m, 2H), 3.88 (td, J=8.72, 3.03 Hz, 1H), 3.95-4.07 (m, 2H), 4.07-4.17(m, 2H), 4.25 (td, J=9.22, 3.41 Hz, 1H), 7.25-7.33 (m, 2H), 7.42-7.46(m, 2H), 7.51 (t, J=1.77 Hz, 1H), 7.53-7.60 (m, 2H).

Compound 30, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.59-1.71 (m, 1H), 1.77-1.91(m, 4H), 2.33 (ddd, J=7.83, 6.06 2.27 Hz, 1H), 3.01-3.20 (m, 6H), 3.28(dd, J=9.22, 3.16 Hz, 1H), 3.67 (t, J=13.52 Hz, 2H), 3.89 (td, J=8.08,6.06 Hz, 1H), 3.96-4.15 (m, 4H), 4.25 (dt, J=9.09, 3.79 Hz, 1H), 7.30(td, J=4.67, 2.53 Hz, 1H), 7.50 (d, J=1.26 Hz, 1H), 7.53-7.59 (m, 2H),7.77 (d, J=7.33 Hz, 1H), 8.04 (d, J=7.58 Hz, 1H).

Compound 31, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.68 (td, J=12.63, 4.80 Hz,1H), 1.79-1.98 (m, 5H), 2.26-2.37 (m, 1H), 2.66-2.83 (m, 2H), 3.09-3.20(m, 4H), 3.27 (bs, 1H), 3.40-3.52 (m, 2H), 3.89 (td, J=8.65, 2.40 Hz,1H), 3.97-4.08 (m, 2H), 4.08-4.15 (m, 2H), 4.25 (bs, 1H), 7.26-7.35 (m,1H), 7.50 (s, 1H), 7.57 (d, J=5.05 Hz, 2H), 7.61 (t, J=7.83 Hz, 1H),7.67-7.74 (m, 2H), 7.77 (t, J=1.77 Hz, 1H).

Compound 32, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.65 (td, J=10.74, 3.92 Hz,1H), 1.76-1.90 (m, 4H), 2.30 (ddd, J=13.52, 8.21, 2.27 Hz, 1H),2.66-2.83 (m, 2H), 2.92 (s, 3H), 3.11 (s, 3H), 3.12-3.20 (m, 1H),3.25-3.30 (m, 1H), 3.34-3.40 (m, 2H), 3.90 (td, J=9.22, 3.79 Hz, 1H),3.96-4.08 (m, 2H), 4.08-4.15 (m, 2H), 4.26 (dt, J=9.35, 3.28 Hz, 1H),4.32 (t, J=4.55 Hz, 2H), 6.84 (d, J=8.34 Hz, 1H), 6.96 (d, J=2.27 Hz,1H), 6.97-7.01 (m, 1H), 7.27-7.34 (m, 1H), 7.50 (t, J=1.26 Hz, 1H), 7.56(d, J=5.05 Hz, 2H).

Compound 33, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.60-1.71 (m, 1H), 1.75-1.92(m, 4H), 2.29 (dd, J=13.77, 8.21 Hz, 1H), 2.74-2.89 (m, 2H), 3.10 (s,3H), 3.15 (d, J=9.85 Hz, 1H), 3.25 (dd, J=12.76, 3.16 Hz, 1H), 3.42-3.56(m, 2H), 3.79-3.88 (m, 1H), 3.93-4.01 (m, 2H), 4.04-4.13 (m, 2H),4.18-4.26 (m, 1H), 7.24-7.31 (m, 1H), 7.49 (d, J=1.52 Hz, 1H), 7.51-7.58(m, 2H), 7.63-7.73 (m, 2H), 7.77 (dd, J=8.72, 1.89 Hz, 1H), 8.01 (d,J=8.08 Hz, 1H), 8.08 (d, J=8.59 Hz, 2H), 8.38 (d, J=1.52 Hz, 1H).

Compound 34, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61-1.71 (m, 1H), 1.78-1.96(m, 4H), 2.29 (dd, J=13.77, 8.21 Hz, 1H), 2.81 (qt, J=12.25, 3.03 Hz,2H), 3.05-3.15 (m, 1H), 3.24-3.27 (m, 1H), 3.34-3.37 (m, 1H), 3.40 (t,J=6.32 Hz, 2H), 3.45-3.55 (m, 2H), 3.85 (t, J=6.19 Hz, 3H), 3.93-4.03(m, 2H), 4.09 (dd, J=4.93, 2.40 Hz, 2H), 4.18-4.26 (m, 1H), 7.29 (ddd,J=6.25, 2.97, 2.65 Hz, 1H), 7.47 (t, J=1.26 Hz, 1H), 7.51-7.57 (m, 2H),7.62-7.74 (m, 2H), 7.78 (dd, J=8.59, 1.77 Hz, 1H), 8.01 (d, J=7.83 Hz,1H), 8.09 (d, J=8.84 Hz, 2H), 8.38 (s, 1H).

Compound 36, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.50 (t, J=7.33 Hz, 3H), 1.68(dd, J=11.24, 4.17 Hz, 1H), 1.77-1.95 (m, 4H), 2.31 (ddd, J=7.96, 6.32,5.94 Hz, 1H), 2.69-2.86 (m, 2H), 3.08-3.19 (m, 4H), 3.23-3.29 (m, 1H),3.40-3.53 (m, 2H), 3.87 (td, J=8.46, 5.94 Hz, 1H), 3.95-4.06 (m, 2H),4.10 (dd, J=4.93, 2.40 Hz, 2H), 4.24 (q, J=7.33 Hz, 3H), 7.30 (td,J=4.61, 2.65 Hz, 1H), 7.50 (d, J=1.52 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H),7.58-7.63 (m, 2H), 7.83-7.94 (m, 3H), 8.14 (s, 1H).

Compound 37, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.68 (td, J=10.99, 4.17 Hz,1H), 1.78-1.95 (m, 4H), 2.31 (ddd, J=13.77, 8.21, 1.77 Hz, 1H),2.70-2.87 (m, 2H), 3.08-3.19 (m, 4H), 3.27 (ddd, J=9.98, 3.03, 2.91 Hz,1H), 3.40-3.53 (m, 2H), 3.87 (td, J=8.46, 5.94 Hz, 1H), 3.94-4.05 (m,2H), 4.10 (dd, J=5.05, 2.27 Hz, 2H), 4.20-4.29 (m, 1H), 7.25-7.33 (m,1H), 7.50 (d, J=1.52 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H), 7.61 (d, J=5.31Hz, 2H), 7.86-7.94 (m, 2H), 8.07 (s, 2H).

Compound 38, ¹H NMR (400 MHz, CD₃OD) δ ppm 0.94 (t, J=7.33 Hz, 3H), 1.68(td, J=10.99, 4.17 Hz, 1H), 1.78-1.97 (m, 6H), 2.31 (ddd, J=13.77, 8.21,1.77 Hz, 1H), 2.70-2.86 (m, 2H), 3.08-3.18 (m, 4H), 3.24-3.29 (m, 1H),3.38-3.53 (m, 2H), 3.87 (td, J=8.46, 5.94 Hz, 1H), 3.94-4.06 (m, 2H),4.08-4.12 (m, 2H), 4.15 (t, J=6.95 Hz, 2H), 4.24 (dt, J=9.09, 3.54 Hz,1H), 7.25-7.33 (m, 1H), 7.50 (t, J=1.52 Hz, 1H), 7.56 (d, J=5.31 Hz,2H), 7.59-7.62 (m, 2H), 7.84-7.93 (m, 3H), 8.14 (s, 1H).

Compound 39, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.05-1.11 (m, 2H), 1.11-1.18(m, 2H), 1.68 (td, J=10.99, 4.42 Hz, 1H), 1.77-1.96 (m, 4H), 2.31 (dd,J=13.52, 7.96 Hz, 1H), 2.69-2.86 (m, 2H), 3.08-3.19 (m, 4H), 3.24-3.29(m, 2H), 3.39-3.52 (m, 2H), 3.66-3.76 (m, 1H), 3.83-3.92 (m, 1H),3.94-4.05 (m, 2H), 4.10 (dd, J=4.80, 2.53 Hz, 2H), 4.19-4.27 (m, 1H),4.54 (bs, 1H), 7.26-7.36 (m, 1H), 7.50 (d, J=1.52 Hz, 1H), 7.56 (d,J=5.05 Hz, 2H), 7.58-7.63 (m, 2H), 7.84-7.94 (m, 3H), 8.18 (s, 1H).

Compound 40, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.68 (td, J=10.86, 4.04 Hz,1H), 1.78-1.95 (m, 4H), 2.31 (ddd, J=13.77, 8.21, 1.77 Hz, 1H),2.70-2.85 (m, 2H), 3.09-3.18 (m, 4H), 3.24-3.29 (m, 1H), 3.46 (t,J=12.76 Hz, 2H), 3.87 (td, J=8.72, 3.03 Hz, 1H), 3.95 (s, 3H), 3.97-4.05(m, 2H), 4.06-4.14 (m, 2H), 4.24 (dt, J=9.09, 3.54 Hz, 1H), 7.26-7.33(m, 1H), 7.50 (d, J=1.52 Hz, 1H), 7.56 (d, J=5.31 Hz, 2H), 7.58-7.62 (m,2H), 7.82-7.91 (m, 3H), 8.09 (s, 1H).

Compound 41, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.69 (td, J=11.12, 4.04 Hz,1H), 1.77-1.97 (m, 4H), 2.32 (ddd, J=13.71, 8.27, 2.27 Hz, 1H), 2.78(qd, J=11.94, 2.91 Hz, 2H), 3.09-3.19 (m, 4H), 3.25-3.29 (m, 1H),3.43-3.55 (m, 2H), 3.88 (td, J=8.59, 5.81 Hz, 1H), 3.96-4.06 (m, 2H),4.10 (dd, J=4.93, 2.40 Hz, 2H), 4.19 (s, 2H), 4.22-4.29 (m, 1H),7.26-7.34 (m, 1H), 7.49 (t, J=1.26 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H),7.60 (d, J=8.34 Hz, 2H), 7.69-7.82 (m, 4H), 7.93-8.01 (m, 2H).

Compound 42, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.69 (td, J=11.24, 4.42 Hz,1H), 1.79-1.98 (m, 4H), 2.32 (ddd, J=13.77, 8.21, 1.77 Hz, 1H),2.70-2.85 (m, 2H), 3.09-3.19 (m, 4H), 3.24-3.29 (m, 1H), 3.44-3.56 (m,2H), 3.87 (td, J=8.46, 5.94 Hz, 1H), 3.95-4.05 (m, 2H), 4.10 (dd,J=4.93, 2.40 Hz, 2H), 4.19-4.28 (m, 1H), 7.26-7.33 (m, 1H), 7.50 (d,J=1.52 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H), 7.75 (t, J=7.96 Hz, 1H),7.81-7.89 (m, 3H), 7.98-8.06 (m, 4H).

Compound 44, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.63-1.74 (m, 1H), 1.80-1.99(m, 4H), 2.33 (ddd, J=7.26, 5.46, 1.77 Hz, 5H), 2.70-2.85 (m, 4H),3.08-3.20 (m, 2H), 3.24-3.30 (m, 2H), 3.50-3.61 (m, 1H), 3.82-3.91 (m,1H), 3.96-4.06 (m, 2H), 4.06-4.15 (m, 2H), 4.19-4.28 (m, 1H), 7.26-7.33(m, 1H), 7.49 (t, J=1.01 Hz, 1H), 7.56 (d, J=5.31 Hz, 2H), 7.86 (t,J=7.83 Hz, 1H), 7.99 (dt, J=8.08, 1.26, 1.01 Hz, 1H), 8.04 (d, J=5.81Hz, 1H), 8.12 (s, 1H), 8.19 (d, J=7.83 Hz, 1H), 8.22 (t, J=1.64 Hz, 1H),8.69 (d, J=6.06 Hz, 1H).

Compound 45, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.62-1.73 (m, 1H), 1.78-1.97(m, 4H), 2.31 (ddd, J=13.77, 8.21, 2.02 Hz, 1H), 2.73-2.89 (m, 2H), 3.11(s, 3H), 3.12-3.18 (m, 1H), 3.24-3.29 (m, 1H), 3.42-3.58 (m, 2H),3.83-3.90 (m, 1H), 3.95-4.05 (m, 2H), 4.06-4.13 (m, 2H), 4.19-4.27 (m,1H), 7.25-7.33 (m, 1H), 7.46-7.51 (m, 2H), 7.54-7.58 (m, 2H), 7.76 (t,J=7.83 Hz, 1H), 7.87 (dt, J=7.83, 1.39 Hz, 1H), 7.96-8.04 (m, 2H), 8.27(dt, J=7.83, 1.39 Hz, 1H), 8.39 (t, J=1.64 Hz, 1H), 8.70 (dt, J=4.86,1.36 Hz, 1H).

Compound 46, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61-1.72 (m, 1H), 1.79-1.96(m, 4H), 2.33 (ddd, J=13.89, 8.34, 2.02 Hz, 1H), 2.69-2.84 (m, 2H),3.09-3.20 (m, 4H), 3.24-3.30 (m, 1H), 3.44-3.60 (m, 2H), 3.84-3.94 (m,1H), 3.98-4.08 (m, 2H), 4.11 (dd, J=4.93, 2.40 Hz, 2H), 4.21-4.29 (m,1H), 7.25-7.34 (m, 1H), 7.50 (t, J=1.26 Hz, 1H), 7.57 (d, J=5.05 Hz,2H), 7.68 (dd, J=8.08, 4.80 Hz, 1H), 8.21 (dd, J=8.21, 1.89 Hz, 1H),8.85 (bs, 1H), 8.94 (bs, 1H).

Compound 47, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.59-1.70 (m, 1H), 1.77-1.94(m, 4H), 2.30 (ddd, J=13.77, 8.21, 2.27 Hz, 1H), 2.66-2.81 (m, 2H), 3.11(s, 3H), 3.16 (t, J=9.47 Hz, 1H), 3.28 (dd, J=9.47, 3.16 Hz, 1H), 3.43(t, J=12.63 Hz, 2H), 3.88 (td, J=8.72, 5.94 Hz, 1H), 3.95-4.06 (m, 2H),4.10 (dd, J=4.93, 1.89 Hz, 2H), 4.25 (dt, J=9.09, 3.54 Hz, 1H),7.25-7.34 (m, 1H), 7.50 (t, J=1.26 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H),7.59-7.64 (m, 2H), 7.65-7.71 (m, 1H), 7.74-7.81 (m, 2H).

Compound 48, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.58-1.70 (m, 1H), 1.77-1.94(m, 4H), 2.31 (ddd, J=13.83, 8.27, 2.15 Hz, 1H), 2.45 (s, 3H), 2.67-2.79(m, 2H), 3.11 (s, 3H), 3.16 (t, J=9.47 Hz, 1H), 3.25-3.30 (m, 1H), 3.42(t, J=12.76 Hz, 2H), 3.88 (td, J=8.59, 6.06 Hz, 1H), 3.94-4.07 (m, 2H),4.11 (dd, J=4.93, 2.15 Hz, 2H), 4.25 (dt, J=9.22, 3.41 Hz, 1H),7.26-7.34 (m, 1H), 7.45-7.52 (m, 3H), 7.53-7.63 (m, 4H).

Compound 49, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.59-1.71 (m, 1H), 1.78-1.94(m, 4H), 2.31 (ddd, J=13.83, 8.27, 2.15 Hz, 1H), 2.68-2.84 (m, 2H), 3.11(s, 3H), 3.16 (t, J=9.47 Hz, 1H), 3.25-3.30 (m, 1H), 3.43 (t, J=13.01Hz, 2H), 3.84-3.93 (m, 4H), 3.96-4.07 (m, 2H), 4.11 (dd, J=4.93, 2.15Hz, 2H), 4.21-4.29 (m, 1H), 7.21-7.36 (m, 4H), 7.49-7.60 (m, 4H).

Compound 50, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.62-1.71 (m, 1H), 1.78-1.96(m, 4H), 2.32 (ddd, J=13.83, 8.27, 1.89 Hz, 1H), 2.67-2.82 (m, 2H), 3.11(s, 3H), 3.16 (t, J=9.22 Hz, 1H), 3.24-3.30 (m, 1H), 3.44-3.58 (m, 2H),3.84-3.92 (m, 1H), 3.96-4.07 (m, 2H), 4.11 (dd, J=4.93, 2.40 Hz, 2H),4.25 (dt, J=8.84, 3.54 Hz, 1H), 7.27-7.33 (m, 1H), 7.50 (t, J=1.77 Hz,1H), 7.54-7.61 (m, 2H), 7.85 (t, J=7.96 Hz, 1H), 7.98-8.04 (m, 2H), 8.06(d, J=7.83 Hz, 1H).

Compound 51, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.65-1.76 (m, 1H), 1.82-2.00(m, 4H), 2.34 (ddd, J=13.64, 8.21, 2.15 Hz, 1H), 2.81-2.97 (m, 2H), 3.11(s, 3H), 3.17 (t, J=9.60 Hz, 1H), 3.26-3.30 (m, 1H), 3.47 (t, J=12.63Hz, 2H), 3.91 (td, J=9.16, 3.92 Hz, 1H), 3.98-4.14 (m, 4H), 4.25 (dt,J=9.22, 3.41 Hz, 1H), 7.27-7.33 (m, 1H), 7.37-7.52 (m, 5H), 7.54-7.56(m, 2H), 7.56 (s, 1H), 7.65-7.72 (m, 2H).

Compound 52, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.62-1.72 (m, 1H), 1.82-1.94(m, 4H), 2.31-2.41 (m, 4H), 2.63 (s, 3H), 2.87-3.03 (m, 2H), 3.12 (s,3H), 3.18 (ddd, J=12.38, 9.35, 9.09 Hz, 1H), 3.32-3.37 (m, 1H),3.41-3.52 (m, 2H), 3.91-3.99 (m, 1H), 4.00-4.17 (m, 4H), 4.23-4.32 (m,1H), 7.26-7.36 (m, 1H), 7.51 (t, J=1.26 Hz, 1H), 7.54-7.60 (m, 2H).

Compound 53, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61-1.71 (m, 1H), 1.78-1.95(m, 4H), 2.32 (ddd, J=13.83, 8.27, 2.15 Hz, 1H), 2.66-2.81 (m, 2H), 3.11(s, 3H), 3.17 (t, J=9.60 Hz, 1H), 3.26-3.30 (m, 1H), 3.41 (t, J=12.76Hz, 2H), 3.89 (td, J=8.34, 5.81 Hz, 1H), 3.97-4.08 (m, 2H), 4.11 (dd,J=4.93, 2.40 Hz, 2H), 4.20-4.31 (m, 1H), 4.70 (s, 2H), 7.13 (d, J=8.59Hz, 1H), 7.27-7.33 (m, 2H), 7.37 (dd, J=8.46, 2.15 Hz, 1H), 7.50 (t,J=1.26 Hz, 1H), 7.53-7.60 (m, 2H).

Compound 54, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.58-1.71 (m, 1H), 1.77-1.95(m, 4H), 2.32 (ddd, J=13.77, 8.34, 2.15 Hz, 1H), 2.69-2.84 (m, 2H), 3.11(s, 3H), 3.17 (t, J=9.35 Hz, 1H), 3.25-3.30 (m, 1H), 3.39-3.53 (m, 2H),3.89 (td, J=8.46, 5.94 Hz, 1H), 3.96-4.08 (m, 2H), 4.11 (dd, J=4.93,2.15 Hz, 2H), 4.25 (dt, J=9.09, 3.28 Hz, 1H), 7.26-7.34 (m, 1H),7.40-7.48 (m, 1H), 7.49-7.54 (m, 2H), 7.57 (d, J=5.05 Hz, 2H), 7.59-7.69(m, 2H).

Compound 55, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.60-1.72 (m, 1H), 1.79-1.95(m, 4H), 2.32 (ddd, J=13.77, 8.34, 2.15 Hz, 1H), 2.69-2.85 (m, 2H), 3.12(s, 3H), 3.17 (t, J=9.47 Hz, 1H), 3.26-3.30 (m, 1H), 3.43-3.54 (m, 2H),3.89 (td, J=8.46, 5.94 Hz, 1H), 3.96-4.07 (m, 2H), 4.11 (dd, J=5.05,2.27 Hz, 2H), 4.26 (dt, J=9.09, 3.54 Hz, 1H), 7.25-7.34 (m, 1H), 7.50(t, J=1.26 Hz, 1H), 7.56 (d, J=5.05 Hz, 2H), 7.81 (t, J=7.71 Hz, 1H),8.05 (dddd, J=11.05, 7.96, 1.33, 1.14 Hz, 2H), 8.15 (t, J=1.52 Hz, 1H).

Compound 63, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.71 (td, J=11.24, 4.17 Hz,1H), 1.80-2.00 (m, 4H), 2.34 (ddd, J=13.39, 7.96, 1.64 Hz, 1H),2.70-2.89 (m, 2H), 3.07-3.20 (m, 4H), 3.24-3.29 (m, 1H), 3.50-3.61 (m,2H), 3.83-3.93 (m, 1H), 3.98-4.08 (m, 2H), 4.11 (dd, J=4.93, 1.89 Hz,2H), 4.26 (bs, 1H), 7.23-7.37 (m, 1H), 7.50 (d, J=1.26 Hz, 1H),7.53-7.60 (m, 2H), 7.87 (t, J=7.83 Hz, 1H), 7.98 (d, J=8.08 Hz, 1H),8.14 (d, J=7.83 Hz, 1H), 8.18-8.28 (m, 2H), 8.92 (bs, 1H), 8.98 (d,J=8.34 Hz, 1H), 9.29 (bs, 1H).

Compound 106, ¹H NMR (400 MHz, CDCl₃) δ ppm 1.30 (s, 6H), 1.56 (dd,J=13.01, 5.18 Hz, 1H), 1.72 (dd, J=7.58, 4.04 Hz, 2H), 1.81-1.89 (m,2H), 2.00 (dd, J=13.14, 7.33 Hz, 1H), 2.67-2.75 (m, 1H), 2.76-2.88 (m,3H), 3.40 (dd, J=7.07, 5.56 Hz, 1H), 3.52 (dd, J=9.22, 4.93 Hz, 1H),3.56-3.65 (m, 2H), 3.73 (s, 2H), 3.82 (dd, J=9.22, 5.68 Hz, 1H),3.97-4.04 (m, 3H), 5.30 (s, 2H), 7.16-7.23 (m, 1H), 7.34-7.38 (m, 1H),7.43-7.52 (m, 2H), 7.66-7.73 (m, 1H), 7.90 (ddd, J=8.53, 7.01, 1.39 Hz,1H), 7.96 (d, J=8.08 Hz, 1H), 8.20 (d, J=8.59 Hz, 1H), 8.60 (d, J=1.77Hz, 1H), 9.17 (d, J=2.27 Hz, 1H).

Compound 107, ¹H NMR (400 MHz, CDC13) δ ppm 1.56 (dd, J=13.01, 5.18 Hz,1H), 1.69-1.76 (m, 2H), 1.81-1.89 (m, 2H), 1.94-2.07 (m, 6H), 2.64-2.76(m, 3H), 2.76-2.87 (m, 3H), 3.35-3.44 (m, 1H), 3.52 (dd, J=9.09, 4.80Hz, 1H), 3.57-3.65 (m, 2H), 3.78-3.86 (m, 3H), 3.96-4.04 (m, 3H),7.15-7.22 (m, 1H), 7.34-7.39 (m, 1H), 7.43-7.51 (m, 2H), 7.65-7.73 (m,1H), 7.90 (ddd, J=8.53, 7.01, 1.39 Hz, 1H), 7.96 (d, J=8.34 Hz, 1H),8.21 (d, J=8.34 Hz, 1H), 8.60 (d, J=1.77 Hz, 1H), 9.17 (d, J=2.27 Hz,1H).

Compound 108, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.29 (s, 6H), 1.31-1.37 (m,1H), 1.55-1.64 (m, 2H), 1.68-1.76 (m, 2H), 1.76-1.81 (m, 2H), 1.90 (dd,J=12.88, 7.58 Hz, 1H), 2.61-2.69 (m, 2H), 2.70-2.78 (m, 2H), 2.82-2.96(m, 2H), 3.33-3.43 (m, 1H), 3.60-3.70 (m, 2H), 3.75-3.83 (m, 1H), 3.99(bs, 4H), 4.55 (s, 1H), 7.25 (ddd, J=8.08, 2.53, 1.26 Hz, 1H), 7.34-7.38(m, 1H), 7.40-7.45 (m, 1H), 7.45-7.51 (m, 1H), 7.74-7.82 (m, 1H), 7.98(ddd, J=8.53, 7.01, 1.39 Hz, 1H), 8.17 (d, J=9.60 Hz, 2H), 8.82 (d,J=2.27 Hz, 1H), 9.12 (d, J=2.27 Hz, 1H).

Compound 109, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.28 (s, 6H), 1.61-1.71 (m,1H), 1.77-1.95 (m, 4H), 2.30 (dd, J=13.77, 7.96 Hz, 1H), 2.75-2.90 (m,2H), 3.14 (dd, J=12.63, 9.60 Hz, 1H), 3.22-3.29 (m, 1H), 3.46-3.58 (m,2H), 3.65 (s, 2H), 3.81-3.90 (m, 1H), 3.92-4.02 (m, 2H), 4.04-4.12 (m,2H), 4.20-4.28 (m, 1H), 7.27-7.33 (m, 1H), 7.38-7.42 (m, 1H), 7.44-7.50(m, 1H), 7.54 (t, J=7.96 Hz, 1H), 7.74 (dd, J=8.34, 4.29 Hz, 1H), 8.09(dd, J=8.84, 2.02 Hz, 1H), 8.25 (d, J=9.09 Hz, 1H), 8.51 (d, J=2.02 Hz,1H), 8.64 (d, J=7.33 Hz, 1H), 9.07 (bs, 1H).

Compound 110, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61-1.71 (m, 1H), 1.77-1.91(m, 4H), 1.92-2.02 (m, 2H), 2.05-2.15 (m, 2H), 2.30 (dd, J=13.77, 7.96Hz, 1H), 2.60-2.74 (m, 2H), 2.76-2.91 (m, 2H), 3.14 (dd, J=12.76, 9.73Hz, 1H), 3.23-3.29 (m, 1H), 3.46-3.60 (m, 2H), 3.71 (s, 2H), 3.82-3.90(m, 1H), 3.94-4.02 (m, 2H), 4.03-4.11 (m, 2H), 4.19-4.28 (m, 1H),7.23-7.31 (m, 1H), 7.39-7.43 (m, 1H), 7.45-7.49 (m, 1H), 7.50-7.56 (m,1H), 7.74 (dd, J=8.34, 4.29 Hz, 1H), 8.10 (dd, J=8.84, 2.02 Hz, 1H),8.25 (d, J=8.84 Hz, 1H), 8.52 (d, J=1.77 Hz, 1H), 8.65 (d, J=7.58 Hz,1H), 9.07 (dd, J=4.29, 1.26 Hz, 1H).

Compound 120, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.62-1.73 (m, 1H), 1.81-1.97(m, 4H), 2.32 (dd, J=13.64, 8.08 Hz, 1H), 2.38 (s, 3H), 2.73-2.88 (m,2H), 3.14 (dd, J=12.76, 9.47 Hz, 1H), 3.41 (t, J=6.19 Hz, 2H), 3.45-3.55(m, 2H), 3.82-3.90 (m, 3H), 3.96-4.06 (m, 2H), 4.07-4.15 (m, 2H),4.21-4.30 (m, 1H), 7.27-7.34 (m, 1H), 7.47-7.50 (m, 1H), 7.52-7.61 (m,3H), 7.78-7.83 (m, 1H), 7.83-7.88 (m, 1H), 7.90-7.96 (m, 2H), 8.04 (d,J=7.07 Hz, 1H), 8.54 (d, J=4.29 Hz, 1H).

Compound 125, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.69 (dd, J=11.12, 4.29 Hz,1H), 1.79-1.95 (m, 4H), 2.29 (dd, J=13.64, 8.34 Hz, 1H), 2.73-2.89 (m,2H), 3.09 (dd, J=12.63, 9.60 Hz, 1H), 3.26 (dd, J=12.76, 2.91 Hz, 1H),3.40 (t, J=6.19 Hz, 2H), 3.45-3.56 (m, 2H), 3.84 (t, J=6.32 Hz, 3H),3.92-3.99 (m, 1H), 3.99-4.04 (m, 1H), 4.06-4.12 (m, 2H), 4.18-4.26 (m,1H), 7.26-7.33 (m, 1H), 7.45-7.49 (m, 1H), 7.51-7.56 (m, 2H), 7.78 (t,J=7.83 Hz, 1H), 7.81 (d, J=7.07 Hz, 1H), 7.87-7.91 (m, 1H), 8.15 (t,J=7.96 Hz, 1H), 8.21-8.26 (m, 1H), 8.39-8.44 (m, 1H), 8.49-8.52 (m, 1H).

Compound 126, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.58-1.70 (m, 2H), 1.72-1.78(m, 2H), 1.80-1.86 (m, 2H), 2.09 (dd, J=13.14, 7.83 Hz, 1H), 2.72-2.91(m, 4H), 3.37-3.46 (m, 4H), 3.53 (quin, J=5.81 Hz, 1H), 3.60 (dd,J=9.22, 5.43 Hz, 1H), 3.85 (t, J=6.19 Hz, 2H), 3.91 (dd, J=9.35, 6.06Hz, 1H), 3.98-4.12 (m, 3H), 7.28 (ddd, J=5.18, 2.53, 2.40 Hz, 1H),7.45-7.50 (m, 1H), 7.50-7.56 (m, 2H), 7.67 (dd, J=6.82, 5.05 Hz, 1H),7.79 (t, J=7.71 Hz, 1H), 7.88-7.92 (m, 1H), 7.95-8.00 (m, 1H), 8.04 (d,J=1.77 Hz, 1H), 8.51 (d, J=5.05 Hz, 1H), 8.59 (d, J=2.78 Hz, 1H).

Compound 127, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61-1.69 (m, 2H), 1.72-1.79(m, 1H), 1.81-1.86 (m, 2H), 2.12 (dd, J=13.26, 7.71 Hz, 1H), 2.61 (s,3H), 2.77-2.88 (m, 3H), 2.92-2.96 (m, 1H), 3.40 (t, J=6.19 Hz, 2H),3.39-3.44 (m, 2H), 3.56-3.66 (m, 2H), 3.84 (t, J=6.32 Hz, 2H), 3.89-3.94(m, 1H), 4.01-4.12 (m, 3H), 7.25-7.31 (m, 2H), 7.44-7.47 (m, 1H),7.48-7.55 (m, 2H), 7.72 (t, J=7.71 Hz, 1H), 7.70 (d, J=7.58 Hz, 1H),7.77-7.84 (m, 2H), 8.24 (ddd, J=7.71, 1.52, 1.39 Hz, 1H), 8.35 (t,J=1.64 Hz, 1H).

Compound 128, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61 (dd, J=13.01, 5.94 Hz,1H), 1.67 (dd, J=10.48, 4.17 Hz, 1H), 1.72-1.77 (m, 1H), 1.80-1.84 (m,2H), 2.09 (dd, J=13.14, 7.58 Hz, 1H), 2.41 (s, 3H), 2.72-2.91 (m, 4H),3.37-3.43 (m, 2H), 3.40 (t, J=6.19 Hz, 2H), 3.51-3.63 (m, 2H), 3.84 (t,J=6.32 Hz, 2H), 3.90 (dd, J=9.22, 5.94 Hz, 1H), 4.00-4.10 (m, 3H), 7.27(dt, J=7.14, 2.37 Hz, 1H), 7.45-7.47 (m, 1H), 7.48-7.55 (m, 2H), 7.72(t, J=7.71 Hz, 1H), 7.75-7.79 (m, 1H), 7.79-7.82 (m, 1H), 7.82-7.85 (m,1H), 8.23 (dt, J=7.77, 1.42 Hz, 1H), 8.34 (t, J=1.52 Hz, 1H), 8.51 (d,J=2.27 Hz, 1H).

Compound 129, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.61-1.70 (m, 2H), 1.73-1.79(m, 1H), 1.80-1.85 (m, 2H), 2.12 (dd, J=13.26, 7.45 Hz, 1H), 2.47 (s,3H), 2.76-2.88 (m, 3H), 2.92-2.97 (m, 1H), 3.40 (t, J=6.19 Hz, 2H),3.41-3.45 (m, 2H), 3.58-3.66 (m, 2H), 3.84 (t, J=6.32 Hz, 2H), 3.88-3.95(m, 1H), 4.01-4.12 (m, 3H), 7.26-7.30 (m, 2H), 7.46 (d, J=2.02 Hz, 1H),7.48-7.56 (m, 2H), 7.73 (t, J=7.83 Hz, 1H), 7.78 (bs, 1H), 7.82-7.85 (m,1H), 8.24 (dt, J=7.83, 1.39 Hz, 1H), 8.34 (t, J=1.64 Hz, 1H), 8.51 (d,J=5.05 Hz, 1H).

Compound 134, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.58 (dd, J=13.01, 6.19 Hz,1H), 1.63-1.70 (m, 1H), 1.70-1.77 (m, 1H), 1.78-1.86 (m, 2H), 2.07 (dd,J=13.01, 7.71 Hz, 1H), 2.71 (dd, J=12.13, 7.33 Hz, 1H), 2.76-2.88 (m,3H), 3.36-3.43 (m, 2H), 3.40 (t, J=6.19 Hz, 2H), 3.45-3.53 (m, 1H), 3.57(t, J=4.55 Hz, 1H), 3.84 (t, J=6.32 Hz, 2H), 3.89 (dd, J=9.22, 5.94 Hz,1H), 3.98-4.08 (m, 3H), 7.06 (dd, J=8.08, 2.53 Hz, 1H), 7.27 (ddd,J=7.39, 2.34, 2.15 Hz, 1H), 7.44-7.47 (m, 1H), 7.48-7.56 (m, 2H), 7.73(t, J=7.83 Hz, 1H), 7.84 (ddd, J=8.08, 1.39, 1.14 Hz, 1H), 7.89 (dd,J=7.58, 2.27 Hz, 1H), 8.04 (q, J=8.08 Hz, 1H), 8.32 (dt, J=7.83, 1.39Hz, 1H), 8.41 (t, J=1.64 Hz, 1H).

Compound 136, ¹H NMR (400 MHz, CDCl₃) δ ppm 1.03-1.08 (m, 2H), 1.55-1.63(m, 3H), 1.69-1.74 (m, 2H), 1.82-1.89 (m, 2H), 2.01 (dd, J=13.01, 7.45Hz, 1H), 2.69-2.76 (m, 1H), 2.77-2.87 (m, 3H), 3.37-3.45 (m, 1H), 3.53(dd, J=9.22, 4.93 Hz, 1H), 3.57-3.63 (m, 2H), 3.65 (s, 2H), 3.82 (dd,J=9.09, 5.81 Hz, 1H), 4.02 (s, 3H), 7.14-7.20 (m, 1H), 7.39-7.42 (m,1H), 7.43-7.49 (m, 2H), 7.66-7.74 (m, 1H), 7.90 (ddd, J=8.46, 6.95, 1.26Hz, 1H), 7.96 (d, J=8.08 Hz, 1H), 8.20 (d, J=8.34 Hz, 1H), 8.60 (d,J=2.02 Hz, 1H), 9.17 (d, J=2.27 Hz, 1H).

Compound 146, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.68-1.78 (m, 1H), 1.82-2.01(m, 2H), 2.24-2.47 (m, 5H), 2.89-3.06 (m, 2H), 3.11-3.19 (m, 1H),3.24-3.28 (m, 1H), 3.45-3.55 (m, 1H), 3.63 (t, J=12.63 Hz, 2H),3.87-3.94 (m, 1H), 3.99-4.06 (m, 2H), 4.07-4.16 (m, 3H), 4.22-4.31 (m,1H), 7.30 (dd, J=8.21, 1.64 Hz, 1H), 7.40 (s, 1H), 7.46 (d, J=7.83 Hz,1H), 7.55 (t, J=7.96 Hz, 1H), 8.00 (t, J=7.45 Hz, 1H), 8.22 (t, J=7.58Hz, 1H), 8.28-8.35 (m, 1H), 8.41 (d, J=8.08 Hz, 1H), 9.35 (d, J=1.01 Hz,1H), 9.44 (d, J=1.77 Hz, 1H).

Compound 147, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.05-1.12 (m, 2H), 1.46-1.51(m, 2H), 1.64-1.75 (m, 1H), 1.79-1.98 (m, 4H), 2.33 (dd, J=13.89, 7.83Hz, 1H), 2.77-2.92 (m, 2H), 3.16 (d, J=9.60 Hz, 1H), 3.24-3.29 (m, 1H),3.53-3.65 (m, 2H), 3.71 (s, 2H), 3.83-3.89 (m, 1H), 3.97-4.03 (m, 2H),4.05-4.14 (m, 2H), 4.18-4.28 (m, 1H), 7.28 (ddd, J=7.77, 2.59, 1.52 Hz,1H), 7.46 (d, J=2.27 Hz, 1H), 7.47-7.57 (m, 2H), 8.03 (dd, J=8.46, 4.93Hz, 1H), 8.27-8.33 (m, 1H), 8.34-8.40 (m, 1H), 8.72 (d, J=1.77 Hz, 1H),9.07 (d, J=8.59 Hz, 1H), 9.25 (d, J=1.01 Hz, 1H).

Compound 148, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.64-1.74 (m, 1H), 1.80-1.98(m, 4H), 2.33 (dd, J=13.89, 7.83 Hz, 1H), 2.77-2.92 (m, 2H), 3.15 (dd,J=13.01, 9.73 Hz, 1H), 3.24-3.29 (m, 1H), 3.55-3.67 (m, 2H), 3.82-3.90(m, 1H), 3.96-4.04 (m, 2H), 4.06-4.11 (m, 2H), 4.11-4.19 (m, 2H), 4.25(dd, J=9.47, 3.16 Hz, 1H), 7.43 (dt, J=7.77, 2.05 Hz, 1H), 7.49-7.52 (m,1H), 7.57-7.66 (m, 2H), 8.12 (dd, J=8.46, 5.18 Hz, 1H), 8.33-8.43 (m,2H), 8.78 (d, J=1.52 Hz, 1H), 9.20 (d, J=8.59 Hz, 1H), 9.31 (dd, J=5.05,1.52 Hz, 1H).

Compound 155, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.05-1.13 (m, 2H), 1.46-1.52(m, 2H), 1.62-1.73 (m, 1H), 1.82-1.94 (m, 4H), 2.32-2.41 (m, 1H),2.76-2.92 (m, 2H), 3.04 (s, 3H), 3.14-3.22 (m, 1H), 3.49 (bs, 4H), 3.59(d, J=5.31 Hz, 1H), 3.63-3.69 (m, 2H), 3.72 (s, 2H), 3.75 (d, J=1.01 Hz,1H), 3.94 (d, J=7.58 Hz, 1H), 4.00-4.17 (m, 4H), 4.28 (bs, 1H), 4.63(bs, 2H), 7.26 (s, 1H), 7.30 (d, J=7.58 Hz, 1H), 7.48-7.51 (m, 2H),7.49-7.57 (m, 1H), 7.83 (bs, 1H).

Compound 156, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.63-1.73 (m, 1H), 1.83-1.96(m, 4H), 2.35 (dd, J=13.52, 8.21 Hz, 1H), 2.75-2.84 (m, 1H), 2.84-2.91(m, 1H), 3.02 (s, 3H), 3.18 (dd, J=12.63, 9.60 Hz, 1H), 3.41-3.53 (m,2H), 3.56-3.61 (m, 2H), 3.63-3.69 (m, 3H), 3.71-3.76 (m, 2H), 3.90-3.95(m, 1H), 3.98-4.10 (m, 2H), 4.10-4.19 (m, 3H), 4.28 (td, J=4.74, 3.16Hz, 1H), 4.60 (d, J=4.55 Hz, 2H), 7.24 (d, J=2.02 Hz, 1H), 7.42-7.47 (m,1H), 7.53 (s, 1H), 7.58-7.67 (m, 2H), 7.81 (bs, 1H).

Compound 157, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.47-1.51(m, 2H), 1.63-1.73 (m, 1H), 1.81-1.96 (m, 3H), 2.33 (dd, J=13.64, 8.08Hz, 1H), 2.71-2.85 (m, 2H), 3.16 (dd, J=12.63, 9.60 Hz, 1H), 3.24-3.28(m, 1H), 3.43-3.54 (m, 2H), 3.56-3.60 (m, 2H), 3.64-3.68 (m, 3H),3.71-3.76 (m, 3H), 3.88-3.94 (m, 1H), 3.98-4.06 (m, 2H), 4.10 (dd,J=4.93, 2.15 Hz, 2H), 4.19 (s, 2H), 4.23-4.30 (m, 1H), 7.29 (dt, J=8.53,1.55 Hz, 1H), 7.44-7.50 (m, 1H), 7.50-7.56 (m, 2H), 7.61 (d, J=8.08 Hz,2H), 7.69-7.82 (m, 4H), 7.94-7.99 (m, 2H).

Compound 158, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.49 (t,J=6.95 Hz, 3H), 1.48-1.52 (m, 2H), 1.60-1.68 (m, 1H), 1.78-1.80 (m, 1H),1.81-1.91 (m, 3H), 2.37 (dd, J=13.77, 8.21 Hz, 1H), 3.07-3.22 (m, 2H),3.51-3.62 (m, 3H), 3.63-3.69 (m, 2H), 3.72 (s, 2H), 3.74-3.76 (m, 1H),3.94-3.99 (m, 1H), 4.01-4.07 (m, 1H), 4.08-4.14 (m, 2H), 4.16 (s, 2H),4.23-4.28 (m, 2H), 4.26-4.31 (m, 1H), 7.30 (d, J=8.59 Hz, 2H), 7.47-7.50(m, 1H), 7.51-7.57 (m, 4H), 7.69 (d, J=8.34 Hz, 2H), 7.87 (dd, J=8.72,2.40 Hz, 1H), 8.08 (d, J=2.53 Hz, 1H).

Compound 161, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.48 (t, J=6.82 Hz, 3H),1.59-1.68 (m, 1H), 1.77-1.91 (m, 3H), 2.37 (dd, J=13.26, 7.71 Hz, 1H),3.08-3.23 (m, 2H), 3.51-3.56 (m, 1H), 3.56-3.60 (m, 2H), 3.63-3.69 (m,4H), 3.72-3.76 (m, 2H), 3.95-4.01 (m, 1H), 4.03-4.08 (m, 1H), 4.08-4.12(m, 1H), 4.12-4.15 (m, 2H), 4.17 (s, 2H), 4.25 (q, J=6.99 Hz, 2H),4.29-4.35 (m, 1H), 7.29 (d, J=8.59 Hz, 1H), 7.46 (d, J=7.83 Hz, 1H),7.53 (s, 1H), 7.56 (d, J=8.08 Hz, 2H), 7.59-7.66 (m, 2H), 7.69 (d,J=8.34 Hz, 2H), 7.87 (dd, J=8.59, 2.27 Hz, 1H), 8.07 (d, J=2.27 Hz, 1H).

Compound 162, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07-1.11 (m, 2H), 1.47-1.51(m, 2H), 1.67 (t, J=10.23 Hz, 1H), 1.84 (d, J=13.89 Hz, 1H), 1.89-1.95(m, 3H), 2.36 (dd, J=13.77, 7.96 Hz, 1H), 2.95-3.09 (m, 2H), 3.16 (dd,J=12.38, 9.85 Hz, 1H), 3.56-3.61 (m, 2H), 3.63-3.69 (m, 2H), 3.71-3.75(m, 4H), 3.91-3.96 (m, 1H), 4.00-4.11 (m, 2H), 4.12 (d, J=5.05 Hz, 2H),4.19 (s, 2H), 4.27-4.33 (m, 1H), 7.27-7.32 (m, 1H), 7.42-7.51 (m, 3H),7.52-7.56 (m, 1H), 7.60 (d, J=8.34 Hz, 2H), 7.73 (d, J=8.08 Hz, 2H),7.97 (ddd, J=8.46, 4.42, 2.27 Hz, 1H), 8.02 (dd, J=6.32, 2.27 Hz, 1H).

Compound 164, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.10 (m, 2H), 1.46-1.52(m, 2H), 1.64-1.73 (m, 1H), 1.80-1.98 (m, 3H), 2.31 (dd, J=13.89, 7.83Hz, 1H), 2.69-2.85 (m, 2H), 3.13 (dd, J=12.13, 10.36 Hz, 1H), 3.44-3.55(m, 2H), 3.72 (s, 2H), 3.87 (d, J=6.06 Hz, 1H), 3.97-4.06 (m, 2H),4.07-4.14 (m, 2H), 4.19 (s, 2H), 4.23-4.30 (m, 1H), 7.29 (d, J=7.83 Hz,1H), 7.45-7.56 (m, 3H), 7.60 (d, J=8.08 Hz, 2H), 7.73 (t, J=7.58 Hz,1H), 7.75-7.80 (m, 1H), 7.77 (d, J=8.34 Hz, 2H), 7.95-7.99 (m, 2H).

Compound 168, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 (t, J=6.95 Hz, 3H),1.56 (ddd, J=13.83, 10.29, 3.92 Hz, 1H), 1.64-1.71 (m, 1H), 1.74-1.82(m, 2H), 1.87 (dd, J=12.76, 6.95 Hz, 1H), 2.19 (dd, J=13.01, 8.21 Hz,1H), 2.92-3.10 (m, 3H), 3.12-3.22 (m, 1H), 3.35-3.43 (m, 1H), 3.44-3.53(m, 2H), 3.63-3.73 (m, 2H), 3.80-3.86 (m, 1H), 3.87-3.94 (m, 1H),3.95-4.00 (m, 1H), 4.01-4.14 (m, 3H), 4.17-4.28 (m, 1H), 4.23 (q, J=6.82Hz, 2H), 4.61 (bs, 1H), 5.95 (d, J=4.80 Hz, 1H), 6.11 (t, J=6.57 Hz,1H), 7.35 (d, J=8.84 Hz, 1H), 7.43 (d, J=1.77 Hz, 1H), 7.51 (dd, J=8.21,1.89 Hz, 1H), 7.54-7.61 (m, 1H), 7.57 (d, J=8.08 Hz, 2H), 7.67-7.73 (m,1H), 7.71 (d, J=8.34 Hz, 2H), 7.94 (dd, J=8.59, 2.27 Hz, 1H), 7.98 (d,J=2.53 Hz, 1H), 8.36 (bs, 2H), 8.98 (bs, 1H), 9.34 (bs, 1H).

Compound 169, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.10 (m, 2H),1.33-1.38 (m, 2H), 1.57-1.74 (m, 2H), 1.77-1.90 (m, 2H), 2.21 (dd,J=13.39, 7.83 Hz, 1H), 2.82-3.04 (m, 2H), 3.07-3.18 (m, 1H), 3.44-3.53(m, 3H), 3.62 (s, 2H), 3.65-3.73 (m, 3H), 3.82-3.99 (m, 3H), 4.03-4.11(m, 1H), 4.08 (t, J=5.05 Hz, 2H), 4.23 (dd, J=8.72, 3.66 Hz, 1H), 7.30(dd, J=8.21, 1.89 Hz, 1H), 7.35-7.36 (m, 1H), 7.45 (d, J=8.34 Hz, 1H),7.56 (t, J=7.96 Hz, 1H), 7.59-7.65 (m, 3H), 7.77 (d, J=8.34 Hz, 2H),7.95 (dd, J=6.57, 2.27 Hz, 1H), 8.08 (ddd, J=8.59, 4.55, 2.53 Hz, 1H),8.47 (bs, 2H), 9.15 (bs, 1H), 9.40 (bs, 1H).

Compound 170, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03-1.09 (m, 2H),1.33-1.37 (m, 2H), 1.56-1.65 (m, 1H), 1.66-1.74 (m, 1H), 1.77-1.86 (m,3H), 2.16 (dd, J=13.26, 7.96 Hz, 1H), 2.37 (s, 3H), 2.57-2.71 (m, 2H),2.92-3.02 (m, 1H), 3.04-3.17 (m, 1H), 3.44-3.53 (m, 1H), 3.62 (d, J=2.78Hz, 2H), 3.65-3.73 (m, 1H), 3.75-3.82 (m, 1H), 3.85-3.93 (m, 2H), 4.05(d, J=5.05 Hz, 2H), 4.15-4.22 (m, 1H), 4.84-4.96 (m, 1H), 5.91 (d,J=4.80 Hz, 1H), 7.26-7.36 (m, 4H), 7.42-7.47 (m, 1H), 7.55 (t, J=7.96Hz, 1H), 7.64 (d, J=8.34 Hz, 2H), 7.68-7.77 (m, 2H), 7.87-7.91 (m, 1H),8.01 (dt, J=7.01, 1.80 Hz, 1H), 9.02 (bs, 1H), 9.19 (bs, 1H).

Compound 172, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.05-1.12 (m, 2H), 1.31-1.36(m, 2H), 1.41-1.45 (m, 2H), 1.46-1.52 (m, 3H), 1.58-1.72 (m, 1H),1.77-1.93 (m, 3H), 2.36 (bs, 1H), 3.08-3.23 (m, 2H), 3.50-3.60 (m, 1H),3.59 (q, J=4.72 Hz, 2H), 3.65 (s, 3H), 3.70-3.76 (m, 3H), 3.98 (d,J=9.09 Hz, 1H), 4.03-4.18 (m, 4H), 4.22-4.29 (m, 2H), 4.30 (bs, 1H),7.27-7.34 (m, 2H), 7.44-7.55 (m, 3H), 7.57 (d, J=8.08 Hz, 2H), 7.68 (d,J=8.08 Hz, 2H), 7.87 (d, J=7.33 Hz, 1H), 8.07 (d, J=1.52 Hz, 1H).

Compound 174, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.12 (m, 2H), 1.45-1.52(m, 5H), 1.64 (t, J=10.36 Hz, 1H), 1.81 (d, J=13.64 Hz, 1H), 1.85-1.92(m, 3H), 2.37 (dd, J=13.64, 7.83 Hz, 1H), 3.07-3.20 (m, 2H), 3.48-3.55(m, 1H), 3.56-3.60 (m, 3H), 3.63-3.69 (m, 7H), 3.71-3.77 (m, 3H),3.95-4.00 (m, 1H), 4.06 (bs, 1H), 4.08-4.16 (m, 3H), 4.25 (q, J=6.82 Hz,2H), 4.28-4.33 (m, 1H), 7.29 (t, J=8.59 Hz, 1H), 7.28-7.33 (m, 1H),7.46-7.52 (m, 3H), 7.55 (d, J=8.34 Hz, 2H), 7.65 (d, J=8.34 Hz, 2H),7.86 (dd, J=8.59, 2.27 Hz, 1H), 8.07 (d, J=2.27 Hz, 1H).

Compound 175, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.05-1.12 (m, 2H), 1.48 (d,J=6.57 Hz, 5H), 1.58-1.67 (m, 1H), 1.77-1.92 (m, 3H), 2.05 (s, 3H), 2.36(dd, J=13.77, 7.96 Hz, 1H), 2.88 (t, J=7.33 Hz, 2H), 3.06-3.22 (m, 3H),3.51 (t, J=7.33 Hz, 2H), 3.48-3.55 (m, 1H), 3.56-3.60 (m, 2H), 3.63-3.69(m, 3H), 3.71-3.76 (m, 3H), 3.94-4.00 (m, 1H), 4.01-4.06 (m, 1H),4.07-4.16 (m, 2H), 4.23 (q, J=6.91 Hz, 2H), 4.27-4.33 (m, 1H), 7.24-7.31(m, 2H), 7.32 (d, J=8.08 Hz, 2H), 7.46-7.50 (m, 1H), 7.50-7.56 (m, 4H),7.82 (dd, J=8.72, 2.40 Hz, 1H), 8.03 (d, J=2.27 Hz, 1H).

Compound 176, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.46-1.52(m, 9H), 1.60-1.69 (m, 1H), 1.77-1.95 (m, 3H), 2.36 (dd, J=13.64, 8.34Hz, 1H), 3.06-3.20 (m, 3H), 3.55-3.60 (m, 4H), 3.63-3.69 (m, 2H),3.71-3.76 (m, 4H), 3.94 (dd, J=10.11, 4.29 Hz, 1H), 4.01-4.08 (m, 1H),4.09-4.14 (m, 3H), 4.22-4.28 (m, 2H), 4.26-4.32 (m, 1H), 7.29-7.33 (m,1H), 7.46-7.50 (m, 1H), 7.50-7.54 (m, 2H), 7.55 (d, J=7.07 Hz, 2H),7.64-7.67 (m, 2H), 7.86 (dd, J=8.59, 2.27 Hz, 1H), 8.07 (d, J=2.27 Hz,1H).

Compound 177, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.45-1.52(m, 5H), 1.59-1.68 (m, 1H), 1.80 (d, J=13.89 Hz, 1H), 1.84-1.92 (m, 3H),1.99 (s, 3H), 2.36 (dd, J=13.52, 8.21 Hz, 1H), 2.86 (t, J=7.33 Hz, 2H),3.06-3.21 (m, 3H), 3.47 (t, J=7.33 Hz, 2H), 3.59 (d, J=5.05 Hz, 2H),3.63-3.69 (m, 2H), 3.71-3.76 (m, 3H), 3.94 (dd, J=10.11, 4.29 Hz, 1H),4.00-4.07 (m, 1H), 4.07-4.15 (m, 2H), 4.23 (q, J=6.99 Hz, 2H), 4.26-4.31(m, 1H), 7.26 (d, J=8.84 Hz, 1H), 7.28-7.32 (m, 1H), 7.32 (d, J=8.34 Hz,2H), 7.46-7.50 (m, 1H), 7.50-7.56 (m, 2H), 7.53 (d, J=8.08 Hz, 2H), 7.82(dd, J=8.59, 2.27 Hz, 1H), 8.03 (d, J=2.53 Hz, 1H).

Compound 180, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.04-1.12 (m, 2H), 1.49 (s,6H), 1.62-1.73 (m, 1H), 1.79-1.97 (m, 4H), 2.32 (dd, J=13.26, 7.71 Hz,1H), 2.70-2.85 (m, 2H), 3.09-3.19 (m, 1H), 3.24 (s, 2H), 3.41-3.53 (m,2H), 3.59 (d, J=5.31 Hz, 1H), 3.63-3.69 (m, 2H), 3.70-3.76 (m, 2H),3.85-3.91 (m, 1H), 3.98-4.07 (m, 2H), 4.08-4.14 (m, 2H), 4.23-4.30 (m,1H), 7.26-7.32 (m, 1H), 7.41-7.56 (m, 3H), 7.60 (d, J=8.08 Hz, 2H),7.69-7.79 (m, 4H), 7.93-7.99 (m, 2H).

Compound 181, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.05-1.12 (m, 2H), 1.49-1.50(m, 6H), 1.68 (t, J=11.12 Hz, 1H), 1.80-1.96 (m, 4H), 2.27-2.38 (m, 1H),2.69-2.85 (m, 2H), 3.10-3.19 (m, 1H), 3.25 (s, 2H), 3.42-3.53 (m, 2H),3.56-3.59 (m, 1H), 3.63-3.69 (m, 2H), 3.71-3.77 (m, 2H), 3.90 (d, J=6.57Hz, 1H), 3.97-4.06 (m, 2H), 4.07-4.14 (m, 2H), 4.27 (bs, 1H), 7.29 (d,J=7.58 Hz, 1H), 7.44-7.56 (m, 3H), 7.60 (d, J=8.08 Hz, 2H), 7.68-7.78(m, 4H), 7.94-7.98 (m, 2H).

Compound 182, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.47-1.51(m, 2H), 1.61-1.73 (m, 1H), 1.80-1.98 (m, 4H), 2.33 (dd, J=13.39, 7.83Hz, 1H), 2.71-2.85 (m, 2H), 3.10-3.17 (m, 1H), 3.44-3.55 (m, 2H),3.64-3.76 (m, 1H), 3.72 (s, 2H), 3.85-3.91 (m, 1H), 3.97-4.07 (m, 2H),4.08-4.14 (m, 2H), 4.26 (s, 2H), 4.25-4.30 (m, 1H), 7.26-7.31 (m, 1H),7.44-7.56 (m, 3H), 7.57-7.68 (m, 3H), 7.74 (t, J=7.96 Hz, 1H), 7.83 (d,J=7.83 Hz, 1H), 7.96-8.01 (m, 2H).

Compound 184, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.05-1.11 (m, 2H), 1.34-1.39(m, 2H), 1.40-1.44 (m, 2H), 1.46-1.52 (m, 2H), 1.62-1.73 (m, 1H),1.79-1.97 (m, 4H), 2.32 (dd, J=13.64, 8.08 Hz, 1H), 2.69-2.84 (m, 2H),3.13 (dd, J=12.63, 9.60 Hz, 1H), 3.42-3.55 (m, 2H), 3.63-3.76 (m, 1H),3.72 (s, 2H), 3.85-3.90 (m, 1H), 3.96-4.07 (m, 1H), 4.08-4.14 (m, 2H),4.21-4.29 (m, 1H), 7.29 (ddd, J=7.71, 2.53, 1.64 Hz, 1H), 7.45-7.56 (m,3H), 7.58-7.63 (m, 2H), 7.69-7.81 (m, 4H), 7.94-7.98 (m, 2H).

Compound 185, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.09 (dd, J=12.13, 1.01 Hz,1H), 1.47-1.53 (m, 2H), 1.63-1.73 (m, 1H), 1.79-1.97 (m, 3H), 2.34 (dd,J=13.77, 8.21 Hz, 1H), 2.72-2.90 (m, 2H), 3.17 (dd, J=12.88, 9.60 Hz,1H), 3.46-3.60 (m, 3H), 3.62-3.76 (m, 1H), 3.72 (s, 2H), 3.86-3.95 (m,1H), 3.98-4.14 (m, 4H), 4.21-4.29 (m, 1H), 7.29 (dt, J=8.59, 1.64 Hz,1H), 7.45-7.58 (m, 3H), 8.37 (t, J=2.02 Hz, 1H), 8.89 (bs, 1H), 8.96(bs, 1H).

Compound 186, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.12 (m, 2H), 1.47-1.52(m, 2H), 1.67 (ddd, J=13.89, 10.99, 4.17 Hz, 1H), 1.79-1.95 (m, 4H),2.34 (dd, J=13.52, 8.21 Hz, 1H), 2.73-2.89 (m, 2H), 3.15 (dd, J=12.76,9.47 Hz, 1H), 3.29-3.35 (m, 1H), 3.44-3.56 (m, 2H), 3.56-3.60 (m, 2H),3.66 (d, J=5.31 Hz, 3H), 3.70-3.77 (m, 4H), 3.86-3.92 (m, 1H), 3.98-4.14(m, 4H), 4.21-4.29 (m, 1H), 7.30 (dt, J=7.64, 2.12 Hz, 1H), 7.45-7.58(m, 3H), 8.37 (t, J=2.02 Hz, 1H), 8.89 (s, 1H), 8.96 (s, 1H).

Compound 187, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.29 (s, 6H), 1.49 (t,J=6.95 Hz, 3H), 1.60-1.69 (m, 1H), 1.78-1.84 (m, 1H), 1.85-1.92 (m, 3H),2.36 (dd, J=13.64, 8.34 Hz, 1H), 3.06-3.22 (m, 2H), 3.30-3.37 (m, 1H),3.50-3.62 (m, 3H), 3.65-3.76 (m, 2H), 3.94 (dd, J=10.23, 4.42 Hz, 1H),4.00-4.07 (m, 1H), 4.08-4.15 (m, 3H), 4.16 (s, 2H), 4.22-4.31 (m, 3H),7.29 (d, J=8.59 Hz, 1H), 7.34 (dd, J=6.95, 1.39 Hz, 1H), 7.41-7.45 (m,1H), 7.47-7.50 (m, 1H), 7.53-7.59 (m, 3H), 7.69 (d, J=8.08 Hz, 2H), 7.87(dd, J=8.59, 2.53 Hz, 1H), 8.08 (d, J=2.53 Hz, 1H).

Compound 188, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.05-1.11 (m, 2H), 1.30-1.37(m, 2H), 1.39-1.43 (m, 2H), 1.45-1.53 (m, 2H), 1.48 (t, J=6.06 Hz, 3H),1.59-1.69 (m, 1H), 1.78-1.93 (m, 4H), 2.36 (dd, J=13.64, 8.34 Hz, 1H),3.05-3.22 (m, 3H), 3.50-3.62 (m, 3H), 3.63-3.69 (m, 3H), 3.71-3.77 (m,4H), 3.94 (dd, J=9.98, 4.17 Hz, 1H), 4.00-4.07 (m, 1H), 4.08-4.16 (m,3H), 4.20-4.31 (m, 1H), 4.25 (q, J=6.82 Hz, 2H), 7.26-7.33 (m, 3H),7.46-7.56 (m, 3H), 7.56 (d, J=8.34 Hz, 2H), 7.69 (d, J=8.34 Hz, 2H),7.87 (dd, J=8.59, 2.27 Hz, 1H), 8.07 (d, J=2.27 Hz, 1H).

Compound 190, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.08 (d, J=2.02 Hz, 2H),1.47-1.52 (m, 2H), 1.62-1.76 (m, 2H), 1.79-1.91 (m, 3H), 1.92 (s, 3H),2.30 (dd, J=13.64, 8.34 Hz, 1H), 2.70-2.83 (m, 2H), 2.85 (t, J=7.33 Hz,2H), 3.12 (dd, J=12.00, 10.48 Hz, 1H), 3.28 (d, J=3.03 Hz, 1H), 3.44 (t,J=7.45 Hz, 2H), 3.43-3.52 (m, 3H), 3.71 (s, 2H), 3.83-3.88 (m, 1H),3.95-4.05 (m, 2H), 4.06-4.13 (m, 2H), 4.20-4.27 (m, 1H), 7.25-7.31 (m,1H), 7.36 (d, J=8.34 Hz, 2H), 7.43-7.47 (m, 1H), 7.48-7.56 (m, 2H), 7.60(d, J=8.34 Hz, 2H), 7.69 (d, J=7.83 Hz, 1H), 7.73 (dt, J=7.83, 1.52 Hz,1H), 7.90-7.95 (m, 2H).

Compound 191, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.05-1.10 (m, 2H), 1.47-1.52(m, 2H), 1.61-1.74 (m, 2H), 1.79-1.90 (m, 4H), 1.92 (s, 3H), 2.31 (dd,J=13.89, 8.08 Hz, 1H), 2.70-2.83 (m, 2H), 2.85 (t, J=7.45 Hz, 2H), 3.15(dd, J=12.63, 9.60 Hz, 1H), 3.27 (dd, J=12.76, 3.16 Hz, 1H), 3.44 (t,J=7.33 Hz, 2H), 3.42-3.52 (m, 2H), 3.71 (s, 2H), 3.85-3.90 (m, 1H),3.95-4.04 (m, 2H), 4.06-4.12 (m, 2H), 4.18-4.26 (m, 1H), 7.28 (ddd,J=5.31, 2.53, 2.27 Hz, 1H), 7.36 (d, J=8.34 Hz, 2H), 7.42-7.47 (m, 1H),7.48-7.56 (m, 2H), 7.60 (d, J=8.34 Hz, 2H), 7.69 (d, J=8.08 Hz, 1H),7.73 (dt, J=7.83, 1.52 Hz, 1H), 7.89-7.96 (m, 2H).

Compound 192, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.12 (m, 2H), 1.48-1.52(m, 2H), 1.60-1.69 (m, 1H), 1.78-1.93 (m, 4H), 2.37 (dd, J=13.77, 8.21Hz, 1H), 2.70 (s, 3H), 3.03-3.23 (m, 3H), 3.39-3.51 (m, 2H), 3.63-3.69(m, 1H), 3.72 (s, 2H), 3.73-3.76 (m, 1H), 3.94-3.99 (m, 1H), 4.01-4.07(m, 1H), 4.08-4.16 (m, 3H), 4.23-4.30 (m, 1H), 7.25-7.33 (m, 2H),7.46-7.58 (m, 3H), 7.87 (d, J=8.08 Hz, 1H), 7.92 (d, J=7.83 Hz, 1H).

Compound 193, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.48-1.52(m, 2H), 1.61-1.70 (m, 1H), 1.79-1.94 (m, 3H), 2.32 (dd, J=13.77, 8.21Hz, 1H), 2.64-2.80 (m, 2H), 3.11-3.20 (m, 1H), 3.27 (d, J=3.03 Hz, 1H),3.36-3.46 (m, 2H), 3.55-3.61 (m, 1H), 3.63-3.69 (m, 1H), 3.72 (s, 2H),3.73-3.76 (m, 1H), 3.87-3.93 (m, 1H), 3.96-4.05 (m, 1H), 3.98 (s, 3H),4.07-4.14 (m, 2H), 4.22-4.28 (m, 1H), 7.24 (d, J=8.59 Hz, 1H), 7.29 (dt,J=7.64, 2.12 Hz, 1H), 7.45-7.57 (m, 3H), 7.75 (dd, J=8.84, 2.27 Hz, 1H),7.90 (d, J=2.27 Hz, 1H).

Compound 194, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07-1.11 (m, 2H), 1.48-1.52(m, 2H), 1.60-1.70 (m, 1H), 1.77-1.94 (m, 3H), 2.32 (dd, J=13.89, 8.08Hz, 1H), 2.49 (s, 3H), 2.66-2.81 (m, 2H), 3.13-3.20 (m, 1H), 3.27 (d,J=3.03 Hz, 1H), 3.38-3.49 (m, 1H), 3.56-3.60 (m, 1H), 3.63-3.68 (m, 1H),3.72 (s, 2H), 3.73-3.76 (m, 1H), 3.87-3.92 (m, 1H), 3.96-4.06 (m, 1H),4.06-4.14 (m, 2H), 4.20-4.27 (m, 1H), 7.29 (dt, J=7.52, 2.05 Hz, 1H),7.44-7.57 (m, 4H), 7.68 (d, J=2.02 Hz, 1H), 7.80 (d, J=8.34 Hz, 1H).

Compound 195, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.46-1.52(m, 2H), 1.65-1.75 (m, 1H), 1.81-1.96 (m, 3H), 2.36 (dd, J=13.64, 7.83Hz, 1H), 2.85-2.99 (m, 2H), 3.14-3.22 (m, 1H), 3.53-3.62 (m, 3H),3.64-3.68 (m, 1H), 3.72 (s, 2H), 3.73-3.77 (m, 1H), 3.89-3.96 (m, 1H),4.01-4.09 (m, 1H), 4.08-4.16 (m, 2H), 4.28 (dd, J=8.72, 2.91 Hz, 1H),7.30 (d, J=7.83 Hz, 1H), 7.44-7.58 (m, 3H), 8.06 (dd, J=7.58, 5.56 Hz,1H), 8.66 (d, J=8.08 Hz, 1H), 9.02 (bs, 1H), 9.18 (bs, 1H).

Compound 196, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.48-1.52(m, 2H), 1.61-1.70 (m, 1H), 1.79-1.95 (m, 4H), 2.32 (dd, J=13.64, 8.08Hz, 1H), 2.49 (s, 3H), 2.67-2.80 (m, 2H), 3.14 (dd, J=12.76, 9.47 Hz,1H), 3.37-3.50 (m, 2H), 3.56-3.60 (m, 1H), 3.63-3.69 (m, 1H), 3.72 (s,2H), 3.73-3.76 (m, 1H), 3.85-3.90 (m, 1H), 3.98-4.07 (m, 1H), 4.09-4.14(m, 2H), 4.21-4.29 (m, 1H), 7.29 (dt, J=8.59, 1.64 Hz, 1H), 7.45-7.57(m, 4H), 7.68 (d, J=1.77 Hz, 1H), 7.80 (d, J=8.34 Hz, 1H).

Compound 197, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07-1.12 (m, 2H), 1.49-1.52(m, 2H), 1.63-1.73 (m, 1H), 1.78-1.97 (m, 4H), 2.39 (dd, J=13.52, 8.21Hz, 1H), 2.44 (s, 3H), 3.09-3.25 (m, 3H), 3.32-3.38 (m, 1H), 3.44-3.56(m, 2H), 3.63-3.69 (m, 1H), 3.73 (s, 2H), 3.73-3.76 (m, 1H), 3.93-4.00(m, 1H), 4.02-4.09 (m, 1H), 4.10-4.17 (m, 3H), 4.20 (s, 2H), 4.24-4.31(m, 1H), 7.31 (ddd, J=7.71, 2.53, 1.39 Hz, 1H), 7.39 (d, J=8.08 Hz, 2H),7.43-7.47 (m, 2H), 7.47-7.54 (m, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.92-7.97(m, 1H).

Compound 198, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07-1.11 (m, 2H), 1.33-1.39(m, 2H), 1.41-1.46 (m, 2H), 1.47-1.52 (m, 2H), 1.67 (t, J=10.23 Hz, 1H),1.79-1.97 (m, 4H), 2.35-2.43 (m, 1H), 2.44 (s, 3H), 3.10-3.24 (m, 3H),3.33-3.38 (m, 1H), 3.48 (t, J=13.39 Hz, 2H), 3.56-3.60 (m, 2H),3.63-3.68 (m, 2H), 3.73 (s, 2H), 3.73-3.76 (m, 2H), 3.98 (dd, J=9.98,3.92 Hz, 1H), 4.07 (bs, 1H), 4.10-4.18 (m, 2H), 4.27-4.34 (m, 1H), 7.31(d, J=7.33 Hz, 1H), 7.38 (d, J=8.08 Hz, 2H), 7.43-7.46 (m, 2H),7.47-7.55 (m, 3H), 7.59 (d, J=8.08 Hz, 2H), 7.92-7.99 (m, 1H).

Compound 200, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07-1.11 (m, 2H), 1.48-1.53(m, 2H), 1.60-1.68 (m, 1H), 1.79-1.91 (m, 4H), 2.37 (dd, J=13.64, 8.34Hz, 1H), 2.70 (s, 3H), 3.04-3.20 (m, 3H), 3.32-3.37 (m, 1H), 3.40-3.51(m, 2H), 3.56-3.60 (m, 1H), 3.63-3.69 (m, 1H), 3.72 (s, 2H), 3.72-3.76(m, 1H), 3.92-3.97 (m, 1H), 4.00-4.08 (m, 1H), 4.09-4.16 (m, 2H),4.24-4.30 (m, 1H), 7.26-7.33 (m, 2H), 7.47-7.58 (m, 3H), 7.87 (dd,J=8.08, 1.01 Hz, 1H), 7.91 (d, J=8.08 Hz, 1H).

Compound 201, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07-1.11 (m, 2H), 1.48-1.52(m, 2H), 1.65 (dd, J=13.64, 6.82 Hz, 1H), 1.78-1.93 (m, 4H), 2.32 (dd,J=13.64, 8.08 Hz, 1H), 2.65-2.79 (m, 2H), 3.14 (dd, J=12.63, 9.60 Hz,1H), 3.35-3.46 (m, 2H), 3.56-3.59 (m, 1H), 3.63-3.68 (m, 1H), 3.72 (s,2H), 3.73-3.76 (m, 1H), 3.86-3.90 (m, 1H), 3.98 (s, 3H), 4.01-4.07 (m,1H), 4.08-4.14 (m, 2H), 4.22-4.29 (m, Hz, 1H), 7.24 (d, J=8.84 Hz, 1H),7.27-7.31 (m, 1H), 7.46-7.50 (m, 1H), 7.51-7.57 (m, 2H), 7.75 (dd,J=8.84, 2.27 Hz, 1H), 7.90 (d, J=2.27 Hz, 1H).

Compound 202, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07-1.11 (m, 2H), 1.47-1.51(m, 2H), 1.65-1.76 (m, 1H), 1.83-1.97 (m, 4H), 2.36 (bs, 1H), 2.84-2.99(m, 2H), 3.12-3.20 (m, 1H), 3.52-3.61 (m, 2H), 3.63-3.69 (m, 1H), 3.72(s, 2H), 3.72-3.77 (m, 1H), 3.92 (d, J=8.34 Hz, 1H), 4.01-4.17 (m, 3H),4.29 (bs, 1H), 7.31 (d, J=7.33 Hz, 1H), 7.44-7.57 (m, 3H), 8.10 (bs,1H), 8.69 (d, J=7.58 Hz, 1H), 9.06 (bs, 1H), 9.22 (bs, 1H).

Compound 203, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07-1.12 (m, 2H), 1.48-1.52(m, 2H), 1.63-1.72 (m, 1H), 1.79-1.95 (m, 3H), 2.40 (dd, J=13.77, 8.21Hz, 1H), 2.44 (s, 3H), 3.10-3.25 (m, 4H), 3.32-3.35 (m, 1H), 3.43-3.54(m, 2H), 3.56-3.60 (m, 1H), 3.63-3.69 (m, 2H), 3.73 (s, 2H), 3.72-3.76(m, 1H), 3.96-4.01 (m, 1H), 4.02-4.09 (m, 1H), 4.09-4.16 (m, 3H), 4.20(s, 2H), 4.25-4.32 (m, 1H), 7.31 (dt, J=7.83, 2.02 Hz, 1H), 7.39 (d,J=8.34 Hz, 2H), 7.43-7.47 (m, 2H), 7.48-7.51 (m, 1H), 7.51-7.59 (m, 4H),7.92-7.98 (m, 1H).

Compound 204, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07-1.11 (m, 2H), 1.34-1.39(m, 2H), 1.40-1.45 (m, 2H), 1.48-1.53 (m, 2H), 1.63-1.72 (m, 1H),1.79-1.95 (m, 3H), 2.40 (dd, J=13.89, 8.34 Hz, 1H), 2.44 (s, 3H),3.10-3.24 (m, 3H), 3.44-3.55 (m, 2H), 3.56-3.59 (m, 1H), 3.63-3.69 (m,2H), 3.73 (s, 2H), 3.72-3.76 (m, 1H), 3.96-4.01 (m, 1H), 4.02-4.09 (m,1H), 4.09-4.16 (m, 3H), 4.25-4.31 (m, 1H), 7.31 (ddd, J=7.77, 2.59, 1.52Hz, 1H), 7.39 (d, J=8.34 Hz, 2H), 7.43-7.46 (m, 2H), 7.47-7.51 (m, 1H),7.51-7.56 (m, 2H), 7.58 (d, J=8.34 Hz, 2H), 7.94 (d, J=4.29 Hz, 1H).

Compound 207, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.48-1.51(m, 2H), 1.63-1.71 (m, 1H), 1.79-1.96 (m, 3H), 2.33 (dd, J=13.52, 8.21Hz, 1H), 2.68-2.81 (m, 2H), 3.14 (dd, J=12.63, 9.60 Hz, 1H), 3.32-3.34(m, 1H), 3.38-3.49 (m, 2H), 3.56-3.60 (m, 1H), 3.64-3.68 (m, 2H),3.70-3.76 (m, 1H), 3.72 (s, 2H), 3.88 (t, J=3.03 Hz, 1H), 3.90 (s, 3H),3.97-4.07 (m, 2H), 4.08-4.15 (m, 2H), 4.17 (s, 2H), 4.24-4.30 (m, 1H),7.27-7.31 (m, 1H), 7.32 (d, J=8.84 Hz, 1H), 7.46-7.48 (m, 1H), 7.49-7.55(m, 4H), 7.57-7.61 (m, 2H), 7.64 (d, J=2.27 Hz, 1H), 7.79 (dd, J=8.72,2.40 Hz, 1H).

Compound 208, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.47-1.51(m, 2H), 1.63-1.72 (m, 1H), 1.80-1.96 (m, 3H), 2.33 (dd, J=13.77, 8.21Hz, 1H), 2.67-2.83 (m, 2H), 3.16 (dd, J=12.63, 9.60 Hz, 1H), 3.26-3.33(m, 1H), 3.39-3.48 (m, 2H), 3.56-3.60 (m, 1H), 3.63-3.69 (m, 2H), 3.72(s, 2H), 3.73-3.76 (m, 1H), 3.88-3.93 (m, 1H), 3.90 (s, 2H), 3.97-4.06(m, 2H), 4.08-4.14 (m, 2H), 4.17 (s, 3H), 4.22-4.29 (m, 1H), 7.27-7.31(m, 1H), 7.32 (d, J=0.84 Hz, 1H), 7.45-7.48 (m, 1H), 7.49-7.55 (m, 4H),7.56-7.61 (m, 2H), 7.64 (d, J=2.27 Hz, 1H), 7.79 (dd, J=8.72, 2.40 Hz,1H).

Compound 210, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.63-1.72 (m, 1H), 1.79-1.98(m, 4H), 2.32 (dd, J=13.64, 8.08 Hz, 1H), 2.70-2.86 (m, 2H), 3.03 (t,J=7.71 Hz, 2H), 3.13 (dd, J=12.76, 9.47 Hz, 1H), 3.23 (t, J=7.83 Hz,2H), 3.28-3.30 (m, 1H), 3.42-3.54 (m, 2H), 3.85-3.89 (m, 1H), 3.95-4.06(m, 2H), 4.14 (t, J=14.40 Hz, 2H), 4.11 (d, J=5.56 Hz, 2H), 7.43 (d,J=8.08 Hz, 2H), 7.43-7.46 (m, 1H), 7.50-7.53 (m, 1H), 7.58-7.66 (m, 2H),7.68 (d, J=8.08 Hz, 2H), 7.71 (d, J=7.83 Hz, 1H), 7.75 (dt, J=7.83, 1.39Hz, 1H), 7.91-7.98 (m, 2H).

Compound 211, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.46-1.51(m, 2H), 1.63-1.72 (m, 1H), 1.79-1.97 (m, 4H), 2.32 (dd, J=13.77, 8.21Hz, 1H), 2.69-2.85 (m, 2H), 3.03 (t, J=7.71 Hz, 2H), 3.13 (dd, J=12.63,9.60 Hz, 1H), 3.23 (t, J=7.83 Hz, 2H), 3.43-3.54 (m, 2H), 3.63-3.76 (m,1H), 3.72 (s, 2H), 3.84-3.91 (m, 1H), 3.95-4.06 (m, 2H), 4.07-4.15 (m,2H), 4.23-4.29 (m, 1H), 7.29 (dt, J=8.59, 1.64 Hz, 1H), 7.43 (d, J=8.34Hz, 2H), 7.45-7.47 (m, 1H), 7.48-7.51 (m, 1H), 7.51-7.56 (m, 1H), 7.68(d, J=8.34 Hz, 2H), 7.71 (d, J=7.83 Hz, 1H), 7.75 (dt, J=7.83, 1.52 Hz,1H), 7.92-7.97 (m, 2H).

Compound 212, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.47-1.51(m, 2H), 1.63-1.72 (m, 1H), 1.78-1.96 (m, 4H), 2.32 (dd, J=13.77, 8.21Hz, 1H), 2.71-2.84 (m, 2H), 3.03 (t, J=7.83 Hz, 2H), 3.15 (dd, J=12.76,9.73 Hz, 1H), 3.23 (t, J=7.71 Hz, 2H), 3.27 (d, J=3.03 Hz, 1H),3.42-3.53 (m, 2H), 3.72 (s, 2H), 3.86-3.94 (m, 1H), 3.97-4.05 (m, 2H),4.06-4.15 (m, 2H), 4.22-4.29 (m, 1H), 7.29 (dt, J=6.88, 1.74 Hz, 1H),7.44 (d, J=8.34 Hz, 2H), 7.45-7.48 (m, 1H), 7.48-7.51 (m, 1H), 7.52 (d,J=7.83 Hz, 1H), 7.67 (d, J=8.08 Hz, 2H), 7.71 (d, J=7.83 Hz, 1H),7.74-7.79 (m, 1H), 7.91-7.98 (m, 2H).

Compound 213, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.63-1.72 (m, 1H), 1.79-1.96(m, 4H), 2.32 (dd, J=13.89, 8.08 Hz, 1H), 2.70-2.84 (m, 2H), 3.03 (t,J=7.71 Hz, 2H), 3.16 (dd, J=12.63, 9.60 Hz, 1H), 3.23 (t, J=7.71 Hz,2H), 3.26 (d, J=3.03 Hz, 1H), 3.43-3.53 (m, 2H), 3.87-3.92 (m, 1H),3.97-4.06 (m, 2H), 4.09-4.13 (m, 2H), 4.14 (t, J=14.40 Hz, 2H),4.22-4.30 (m, 1H), 7.42-7.46 (m, 1H), 7.43 (d, J=8.08 Hz, 2H), 7.51-7.52(m, 1H), 7.58-7.61 (m, 1H), 7.62 (d, J=7.83 Hz, 1H), 7.68 (d, J=8.08 Hz,2H), 7.71 (d, 1H), 7.75 (dt, J=8.08, 1.39 Hz, 1H), 7.92-7.96 (m, 2H).

Compound 214, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.44-1.53(m, 2H), 1.48 (t, J=6.95 Hz, 3H), 1.60-1.69 (m, 1H), 1.79-1.92 (m, 4H),2.36 (dd, J=13.64, 8.34 Hz, 1H), 3.01 (t, J=7.71 Hz, 2H), 3.07-3.24 (m,5H), 3.35 (d, J=2.78 Hz, 1H), 3.50-3.61 (m, 2H), 3.72 (s, 2H), 3.94 (dd,J=10.23, 4.17 Hz, 1H), 4.00-4.07 (m, 1H), 4.08-4.15 (m, 2H), 4.25 (q,J=6.99 Hz, 2H), 4.25-4.31 (m, 1H), 7.28 (d, J=8.84 Hz, 1H), 7.29-7.33(m, 1H), 7.38 (d, J=8.08 Hz, 2H), 7.46-7.49 (m, 1H), 7.49-7.52 (m, 1H),7.53 (d, J=7.83 Hz, 1H), 7.60 (d, J=8.34 Hz, 2H), 7.84 (dd, J=8.72, 2.40Hz, 1H), 8.05 (d, J=2.27 Hz, 1H).

Compound 215, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07-1.10 (m, 2H), 1.47-1.52(m, 2H), 1.68 (dd, J=11.12, 4.04 Hz, 1H), 1.79-1.96 (m, 4H), 2.32 (d,J=5.56 Hz, 1H), 2.67-2.82 (m, 2H), 3.02 (t, J=7.71 Hz, 2H), 3.14 (dd,J=12.63, 9.60 Hz, 1H), 3.23 (t, J=7.71 Hz, 2H), 3.33 (d, J=3.03 Hz, 1H),3.37-3.50 (m, 2H), 3.72 (s, 2H), 3.86-3.90 (m, 1H), 3.90 (s, 3H),3.98-4.07 (m, 2H), 4.08-4.15 (m, 2H), 4.23-4.30 (m, 1H), 7.29 (d, J=8.84Hz, 2H), 7.36 (d, J=8.08 Hz, 2H), 7.46-7.57 (m, 5H), 7.62 (d, J=2.27 Hz,1H), 7.76 (dd, J=8.72, 2.40 Hz, 1H).

Compound 216, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.10 (m, 2H), 1.47-1.51(m, 2H), 1.64-1.72 (m, 1H), 1.80-1.97 (m, 4H), 2.34 (dd, J=13.52, 7.96Hz, 1H), 2.71-2.87 (m, 2H), 3.17 (dd, J=12.51, 9.73 Hz, 1H), 3.28 (d,J=2.53 Hz, 1H), 3.43-3.54 (m, 2H), 3.72 (s, 2H), 3.92 (d, J=6.06 Hz,1H), 3.99-4.07 (m, 2H), 4.08-4.14 (m, 2H), 4.21 (s, 2H), 4.27 (dd,J=8.84, 2.78 Hz, 1H), 7.27-7.33 (m, 1H), 7.44-7.50 (m, 2H), 7.51 (s,1H), 7.53 (d, J=7.83 Hz, 1H), 7.59-7.63 (m, 2H), 7.65-7.70 (m, 2H),7.82-7.90 (m, 2H).

Compound 217, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.35-1.40(m, 2H), 1.41-1.46 (m, 2H), 1.47-1.52 (m, 2H), 1.61-1.73 (m, 1H),1.79-1.97 (m, 4H), 2.34 (dd, J=13.64, 7.58 Hz, 1H), 2.65-2.85 (m, 2H),3.17 (dd, J=12.51, 9.73 Hz, 1H), 3.28 (d, J=2.53 Hz, 1H), 3.39-3.54 (m,2H), 3.72 (s, 2H), 3.88-3.96 (m, 1H), 3.98-4.07 (m, 2H), 4.08-4.15 (m,2H), 4.22-4.31 (m, 1H), 7.30 (dt, J=7.77, 1.93 Hz, 1H), 7.45-7.50 (m,2H), 7.50-7.52 (m, 1H), 7.53 (d, J=7.58 Hz, 1H), 7.60-7.63 (m, 2H),7.65-7.70 (m, 2H), 7.80-7.90 (m, 2H).

Compound 218, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.46-1.52(m, 2H), 1.61-1.73 (m, 1H), 1.81-1.98 (m, 4H), 2.34 (dd, J=13.39, 8.08Hz, 1H), 2.70-2.85 (m, 2H), 3.14 (dd, J=12.76, 9.47 Hz, 1H), 3.32-3.35(m, 1H), 3.43-3.55 (m, 2H), 3.72 (s, 2H), 3.86-3.92 (m, 1H), 3.97-4.09(m, 2H), 4.08-4.14 (m, 2H), 4.20 (s, 2H), 4.23-4.31 (m, 1H), 7.30 (td,J=7.77, 2.59, 1.52 Hz, 1H), 7.45-7.50 (m, 2H), 7.50-7.52 (m, 1H),7.52-7.57 (m, 1H), 7.59-7.63 (m, 2H), 7.65-7.69 (m, 2H), 7.81-7.90 (m,2H).

Compound 219, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.35-1.40(m, 2H), 1.42-1.47 (m, 2H), 1.47-1.52 (m, 2H), 1.61-1.72 (m, 1H),1.79-1.97 (m, 4H), 2.33 (dd, J=13.77, 6.69 Hz, 1H), 2.66-2.86 (m, 2H),3.08-3.20 (m, 1H), 3.32-3.35 (m, 1H), 3.42-3.53 (m, 2H), 3.72 (s, 2H),3.86-3.93 (m, 1H), 3.98-4.07 (m, 2H), 4.09-4.16 (m, 2H), 4.23-4.31 (m,1H), 7.27-7.32 (m, 1H), 7.44-7.49 (m, 2H), 7.50-7.56 (m, 2H), 7.60-7.63(m, 2H), 7.65-7.69 (m, 2H), 7.80-7.90 (m, 2H).

Compound 220, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.11 (m, 2H), 1.46-1.53(m, 5H), 1.59-1.71 (m, 1H), 1.82 (d, J=14.15 Hz, 1H), 1.85-1.93 (m, 3H),2.37 (dd, J=13.52, 8.21 Hz, 1H), 3.07-3.22 (m, 3H), 3.56-3.60 (m, 2H),3.63-3.68 (m, 2H), 3.72 (s, 2H), 3.72-3.76 (m, 1H), 3.91-3.97 (m, 1H),4.01-4.07 (m, 1H), 4.09-4.16 (m, 3H), 4.21-4.32 (m, 5H), 7.31 (d, J=8.59Hz, 2H), 7.46-7.62 (m, 6H), 7.90 (dd, J=8.72, 2.40 Hz, 1H), 8.09 (d,J=2.53 Hz, 1H).

Compound 221, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.07-1.12 (m, 2H), 1.48-1.52(m, 2H), 1.63-1.73 (m, 1H), 1.80-1.98 (m, 4H), 2.35 (d, J=5.56 Hz, 1H),2.77-2.85 (m, 1H), 2.85-2.92 (m, 1H), 3.14-3.22 (m, 1H), 3.28 (d, J=3.03Hz, 1H), 3.47-3.60 (m, 2H), 3.73 (s, 2H), 3.90-3.95 (m, 1H), 3.98-4.08(m, 2H), 4.08-4.15 (m, 2H), 4.22-4.30 (m, 1H), 7.30 (ddd, J=7.64, 2.59,1.64 Hz, 1H), 7.45-7.49 (m, 1H), 7.49-7.53 (m, 1H), 7.54 (d, J=7.83 Hz,1H), 8.47 (d, J=2.27 Hz, 1H), 8.72 (d, J=2.27 Hz, 1H).

Compound 223, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.31 (s, 6H), 1.64-1.74 (m,1H), 1.81-1.99 (m, 4H), 2.33 (d, J=13.39 Hz, 1H), 2.69-2.83 (m, 2H),3.16 (dd, J=12.38, 9.60 Hz, 1H), 3.34-3.36 (m, 1H), 3.41-3.51 (m, 3H),3.68-3.70 (m, 1H), 3.87-3.92 (m, 1H), 3.92 (s, 3H), 3.99-4.10 (m, 2H),4.09-4.16 (m, 2H), 4.19 (s, 2H), 4.25-4.33 (m, 1H), 7.30-7.37 (m, 2H),7.43-7.46 (m, 1H), 7.48-7.52 (m, 1H), 7.52-7.63 (m, 5H), 7.65 (d, J=2.27Hz, 1H), 7.81 (dd, J=8.72, 2.15 Hz, 1H).

Compound 224, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.31 (s, 6H), 1.34-1.40 (m,2H), 1.40-1.47 (m, 2H), 1.63-1.72 (m, 1H), 1.81-1.98 (m, 4H), 2.34 (dd,J=13.39, 8.08 Hz, 1H), 2.68-2.84 (m, 2H), 3.16 (dd, J=12.63, 9.60 Hz,1H), 3.35 (d, J=3.03 Hz, 1H), 3.39-3.50 (m, 2H), 3.68-3.71 (m, 1H),3.87-3.91 (m, 2H), 3.92 (s, 3H), 3.99-4.10 (m, 2H), 4.10-4.16 (m, 2H),4.26-4.33 (m, 1H), 7.33 (d, J=8.84 Hz, 1H), 7.33-7.37 (m, 1H), 7.43-7.46(m, 1H), 7.49-7.52 (m, 1H), 7.54-7.61 (m, 5H), 7.65 (d, J=2.27 Hz, 1H),7.80 (dd, J=8.72, 2.40 Hz, 1H).

Compound 225, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06-1.12 (m, 2H), 1.33-1.38(m, 2H), 1.39-1.45 (m, 2H), 1.47-1.52 (m, 2H), 1.62-1.72 (m, 1H),1.79-1.96 (m, 4H), 2.33 (dd, J=13.52, 8.21 Hz, 1H), 2.68-2.82 (m, 2H),3.14 (dd, J=12.63, 9.60 Hz, 1H), 3.32-3.35 (m, 1H), 3.38-3.50 (m, 2H),3.72 (s, 2H), 3.86-3.89 (m, 1H), 3.91 (s, 3H), 3.98-4.07 (m, 2H),4.07-4.15 (m, 2H), 4.23-4.32 (m, 1H), 7.27-7.34 (m, 2H), 7.46-7.48 (m,1H), 7.49-7.60 (m, 6H), 7.63 (d, J=2.53 Hz, 1H), 7.79 (dd, J=8.72, 2.40Hz, 1H).

Compound 233, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.58-1.67 (m, 3H), 1.68-1.76(m, 1H), 1.82-2.00 (m, 4H), 2.34 (dd, J=13.77, 7.96 Hz, 1H), 2.88-3.01(m, 2H), 3.15 (dd, J=12.88, 9.60 Hz, 1H), 3.24-3.30 (m, 1H), 3.56-3.67(m, 2H), 3.85-3.92 (m, 1H), 3.97-4.05 (m, 2H), 4.06-4.14 (m, 2H),4.22-4.30 (m, 1H), 5.45-5.62 (m, 1H), 7.37 (ddd, J=8.08, 2.53, 1.01 Hz,1H), 7.46 (t, J=2.02 Hz, 1H), 7.51-7.56 (m, 1H), 7.59 (d, J=8.08 Hz,1H), 7.93-8.00 (m, 1H), 8.18 (ddd, J=8.59, 7.07, 1.52 Hz, 1H), 8.28 (d,J=8.59 Hz, 1H), 8.36 (d, J=8.08 Hz, 1H), 9.25 (d, J=1.77 Hz, 1H), 9.38(d, J=2.02 Hz, 1H).

Compound 234, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.58-1.67 (m, 3H), 1.68-1.76(m, 1H), 1.82-2.00 (m, 4H), 2.34 (dd, J=13.77, 7.96 Hz, 1H), 2.88-3.01(m, 2H), 3.15 (dd, J=12.88, 9.60 Hz, 1H), 3.24-3.30 (m, 1H), 3.56-3.67(m, 2H), 3.85-3.92 (m, 1H), 3.97-4.05 (m, 2H), 4.06-4.14 (m, 2H),4.22-4.30 (m, 1H), 5.45-5.62 (m, 1H), 7.37 (ddd, J=8.08, 2.53, 1.01 Hz,1H), 7.46 (t, J=2.02 Hz, 1H), 7.51-7.56 (m, 1H), 7.59 (d, J=8.08 Hz,1H), 7.93-8.00 (m, 1H), 8.18 (ddd, J=8.59, 7.07, 1.52 Hz, 1H), 8.28 (d,J=8.59 Hz, 1H), 8.36 (d, J=8.08 Hz, 1H), 9.25 (d, J=1.77 Hz, 1H), 9.38(d, J=2.02 Hz, 1H).

Compound 235, ¹H NMR (400 MHz, CD₃OD) δ ppm 1.64 (dd, J=23.75, 6.57 Hz,3H), 1.68-1.74 (m, 1H), 1.82-1.96 (m, 4H), 2.38 (dd, J=13.52, 7.96 Hz,1H), 2.84-2.99 (m, 2H), 3.10 (s, 3H), 3.15-3.23 (m, 1H), 3.32-3.35 (m,1H), 3.44-3.54 (m, 2H), 3.59 (t, J=4.42 Hz, 2H), 3.91-3.97 (m, 1H),4.01-4.10 (m, 2H), 4.10-4.17 (m, 2H), 4.26-4.34 (m, 1H), 4.75 (t, J=4.42Hz, 2H), 5.49 (dq, J=47.49, 6.32 Hz, 1H), 7.37-7.42 (m, 2H), 7.47-7.51(m, 1H), 7.54-7.56 (m, 1H), 7.61 (t, J=7.96 Hz, 1H), 7.87 (d, J=1.52 Hz,1H).

Example 2 IC50 Determinations in Homogeneous Time-Resolved Fluorescence(HTRF®) cAMP Antagonist Assays

HTRF cAMP assays were performed according to manufacturer's instructions(Cisbio, cAMP Dynamic 2 Assay Kit; #62AM4PEJ). CHO-K1 cells stablyexpressing recombinant receptor were harvested and suspended in warm PBSto make a 300,000 cells/mL stock. This cell suspension was dispensedinto 384 well assay plates (PerkinElmer ProxiPlate #6008280) at 5 μL perwell (1500 cells/well) along with a cAMP standard curve.

Compounds were dissolved and serially diluted (5-fold) in DMSO togenerate a 10-point dose response stock. The stock was then diluted100-fold in assay buffer (PBS containing 1 mM IBMX) before a volume of2.5 μL was added to the cells (the final, top concentration of compoundin the dose-response is typically 10 or 100 μM). After a briefincubation, 2.5 μL of isoproterenol stock, prepared at a concentration 4times its EC₉₀ at the receptor of interest, was added to the wells. TheEC₉₀ for isoproterenol, a beta-adrenergic agonist, was determined inseparate experiments using standard methods to measure agonistpotencies.

Following a 1-hour incubation at room temperature, 5 μL of cAMP-D2Reagent diluted in Lysis Buffer was added to each well followed by 5 μLof Cryptate Reagent. Plates were further incubated at room temperaturefor 1 hour prior to reading. Time resolved fluorescence measurementswere collected on a suitable, HTRF-capable plate reader.

Counts from the plate reader were fit to the cAMP standard curve on theassay plate in order to determine cAMP concentrations in each well, andthese values were used to construct dose-response curves to obtain IC₅₀values.

TABLE B Beta-3 Adrenergic Receptor IC₅₀ Values Cmpd No. IC₅₀ 5 33.31 nM88 25.12 nM 123 53.17 nM 136 18.83 nM 154 17.5 nM 161 21.14 nM 163 17.31nM 169 17.47 nM 199 25.01 nM 210 22.43 nM 211 26.18 nM 217 28.43 nM 22533.1 nM 227 17.9 nM 229 11.58 nM 230 14.99 nM 232 16.63 nM 234 10.19 nM240 31.69 nM 241 21.06 nM 243 35.01 nM 244 27.83 nM 245 18.38 nM 24733.47 nM 296 107.3 nM 297 26.5 nM 300 20.39 nM 309 7.003 nM 310 37.65 nM320 11.18 nM 321 17.83 nM 322 21.77 nM 326 17.26 nM 327 28.92 nM 32929.49 nM 331 30.04 nM

Each of the compounds specifically described herein was observed to havea beta-3 adrenergic receptor IC₅₀ value in the range of about 3.0 nM toabout 2.0 μM.

Specific IC₅₀ values for certain compounds are provided below, where thenumber directly preceeding the IC₅₀ value refers to the compound number(e.g., 1: 4.42 nM refers to Compound 1 with an IC₅₀ value of 4.42 nM):

1: 4.42 nM; 2: 44.79 nM; 3: 5.47 nM; 4: 4.45 nM; 6: 16.46 nM; 7: 34.24nM; 8: 12.08 nM; 9: 24.25 nM; 10: 25.05 nM; 11: 35.52 nM; 12: 130.50 nM;13: 97.85 nM; 14: 56.71 nM; 15: 5.70 nM; 16: 132.70 nM; 17: 38.76 nM;18: 48.93 nM; 19: 66.74 nM; 20: 76.21 nM; 21: 252.30 nM; 22: 302.00 nM;23: 242.00 nM; 24: 23.63 nM; 25: 54.56 nM; 26: 5.25 nM; 27: 19.33 nM;28: 18.52 nM; 29: 16.09 nM; 30: 34.28 nM; 31: 49.26 nM; 32: 21.06 nM;33: 189.20 nM; 34: 31.24 nM; 35: 20.26 nM; 36: 21.51 nM; 37: 9.37 nM;38: 3.99 nM; 39: 70.81 nM; 40: 20.33 nM; 41: 13.68 nM; 42: 18.68 nM; 43:32.42 nM; 44: 21.51 nM; 45: 23.64 nM; 46: 87.03 nM; 47: 82.09 nM; 48:46.11 nM; 49: 33.13 nM; 50: 42.23 nM; 51: 17.36 nM; 52: 61.20 nM; 53:23.93 nM; 54: 45.94 nM; 55: 30.55 nM; 56: 1988.00 nM; 57: 486.90 nM; 58:109.30 nM; 59: 12.30 nM; 60: 17.37 nM; 61: 29.81 nM; 62: 24.46 nM; 63:17.20 nM; 64: 921.70 nM; 65: 710.50 nM; 66: 981.60 nM; 67: 821.90 nM;68: 493.60 nM; 69: 21.25 nM; 70: 24.43 nM; 71: 38.95 nM; 72: 328.70 nM;73: 23.95 nM; 74: 37.97 nM; 75: 26.70 nM; 76: 35.91 nM; 77: 35.08 nM;78: 41.93 nM; 79: 42.20 nM; 80: 38.10 nM; 81: 27.79 nM; 82: 43.23 nM;83: 53.47 nM; 84: 54.69 nM; 85: 17.84 nM; 86: 9.10 nM; 87: 41.12 nM; 89:110.10 nM; 90: 354.30 nM; 91: 37.14 nM; 92: 26.93 nM; 93: 75.04 nM; 94:113.50 nM; 95: 21.09 nM; 96: 410.60 nM; 97: 212.10 nM; 98: 89.00 nM; 99:287.30 nM; 100: 92.16 nM; 101: 466.20 nM; 102: 113.80 nM; 103: 1195.00nM; 104: 36.50 nM; 105: 277.40 nM; 106: 36.24 nM; 107: 25.73 nM; 108:325.30 nM; 109: 144.60 nM; 110: 68.65 nM; 111: 31.07 nM; 112: 39.47 nM;113: 26.79 nM; 114: 51.96 nM; 115: 120.50 nM; 116: 319.70 nM; 117:171.60 nM; 118: 10.44 nM; 119: 11.64 nM; 120: 177.30 nM; 121: 562.40 nM;122: 7.81 nM; 124: 78.20 nM; 125: 48.81 nM; 126: 126.50 nM; 127: 156.60nM; 128: 108.50 nM; 129: 485.00 nM; 130: 12.00 nM; 131: 23.72 nM; 132:739.30 nM; 133: 443.00 nM; 134: 55.13 nM; 135: 88.77 nM; 137: 349.50 nM;138: 20.41 nM; 139: 36.18 nM; 140: 45.89 nM; 141: 11.63 nM; 142: 106.00nM; 143: 13.23 nM; 144: 7.77 nM; 145: 81.89 nM; 146: 103.60 nM; 147:53.32 nM; 148: 21.76 nM; 149: 97.26 nM; 150: 226.60 nM; 151: 40.85 nM;152: 24.68 nM; 153: 18.80 nM; 155: 48.24 nM; 156: 24.78 nM; 157: 25.73nM; 158: 27.29 nM; 159: 177.90 nM; 160: 11.58 nM; 162: 29.51 nM; 164:27.73 nM; 165: 64.38 nM; 166: 51.18 nM; 167: 15.79 nM; 168: 15.38 nM;170: 416.40 nM; 171: 25.03 nM; 172: 50.34 nM; 173: 31.25 nM; 174: 699.30nM; 175: 715.60 nM; 176: 58.42 nM; 177: 50.59 nM; 178: 84.61 nM; 179:49.11 nM; 180: 30.67 nM; 181: 179.70 nM; 182: 24.74 nM; 183: 1600.00 nM;184: 26.72 nM; 185: 257.80 nM; 186: 78.60 nM; 187: 33.40 nM; 188: 35.02nM; 189: 10.31 nM; 190: 31.27 nM; 191: 439.90 nM; 192: 298.30 nM; 193:26.90 nM; 194: 13.65 nM; 195: 1530.00 nM; 196: 34.61 nM; 197: 84.99 nM;198: 62.23 nM; 200: 72.38 nM; 201: 41.80 nM; 202: 345.90 nM; 203:1111.00 nM; 204: 503.80 nM; 205: 92.19 nM; 206: 402.80 nM; 207: 51.11nM; 208: 34.76 nM; 209: 8.79 nM; 212: 25.96 nM; 213: 18.62 nM; 214:36.66 nM; 215: 38.42 nM; 216: 26.42 nM; 218: 29.32 nM; 219: 21.59 nM;220: 27.50 nM; 221: 20.57 nM; 222: 47.57 nM; 223: 83.59 nM; 224: 73.16nM; 226: 12.46 nM; 228: 29.07 nM; 231: 19.61 nM; 233: 9.72 nM; 235:14.97 nM; 236: 368.60 nM; 237: 81.97 nM; 238: 22.84 nM; 239: 30.94 nM;242: 35.50 nM; 246: 48.29 nM; 248: 72.39 nM; 249: 224.40 nM; 250: 335.70nM; 251: 51.62 nM; 252: 29.26 nM; 253: 29.15 nM; 254: 41.77 nM; 255:27.94 nM; 256: 32.64 nM; 257: 37.84 nM; 258: 27.73 nM; 259: 158.30 nM;260: 177.90 nM; 261: 38.77 nM; 262: 981.90 nM; 263: 754.60 nM; 264:979.70 nM; 265: 374.30 nM; 266: 1291.00 nM; 267: 442.30 nM; 268: 138.30nM; 269: 399.70 nM; 270: 92.31 nM; 271: 205.50 nM; 272: 566.10 nM; 273:29.35 nM; 274: 38.43 nM; 275: 62.29 nM; 276: 1808.00 nM; 277: 16.46 nM;278: 585.90 nM; 279: 39.75 nM; 280: 96.39 nM; 281: 57.87 nM; 282: 23.74nM; 283: 68.93 nM; 284: 106.40 nM; 285: 303.30 nM; 286: 56.94 nM; 287:150.50 nM; 288: 176.50 nM; 289: 65.82 nM; 290: 34.18 nM; 291: 69.80 nM;292: 90.25 nM; 293: 130.20 nM; 294: 109.80 nM; 295: 143.20 nM; 298:82.52 nM; 299: 44.31 nM; 301: 357.00 nM; 302: 696.00 nM; 303: 17.11 nM;304: 69.02 nM; 305: 17.11 nM; 306: 62.90 nM; 307: 59.18 nM; 308: 34.50nM; 311: 43.50 nM; 312: 31.55 nM; 313: 141.50 nM; 314: 269.70 nM; 315:23.94 nM; 316: 63.76 nM; 317: 104.00 nM; 318: 95.17 nM; 319: 16.51 nM;323: 49.56 nM; 324: 22.46 nM; 325: 34.05 nM; 328: 35.37 nM; 330: 70.08nM; 332: 42.26 nM; 333: 16.28 nM; 334: 79.94 nM; 335: 14.45 nM; 336:101.70 nM; 337: 1689.00 nM; and 338: 32.15 nM.

Example 3 Ki Determination by Radioligand Binding

Radioligand binding assays are performed using the commerciallyavailable adrenergic receptor agonist [¹²⁵I]Cyanopindolol as theradioligand and non-specific binding is determined in the presence ofunlabeled L-748,337 at a saturating concentration of 10 μM. For thebeta-3 adrenergic receptor, the radioligand is used in the assay at afinal concentration of 0.4 nM. Membrane pellets prepared from CHO-K1cells stably expressing recombinant beta-3 adrenergic receptors areprepared using standard methods and stored at −80° C. Membranes arethawed on ice and resuspended in Assay Buffer (20 mM HEPES, pH 7.4, 10mM MgCl₂) by dounce homogenization. Competition experiments consist ofaddition of 145 μL of membranes, 50 μL of radioligand stock, and 5 μL oftest compound diluted in DMSO to 96-well microtiter plates. Plates areincubated for one hour at room temperature and the assay terminated byrapid filtration through Perkin Elmer GF/C filtration, plates pretreatedwith 0.5% PEI, under vacuum pressure using a 96-well Packard filtrationapparatus. Plates are rapidly washed several times with ice-cold AssayBuffer and then dried overnight at 45° C. Finally, 25 μL of BetaScintscintillation cocktail is added to each well and plates counted in aPackard TopCount scintillation counter. In each competition study, testcompounds are dosed at eight to ten concentrations with triplicatedeterminations at each test concentration. A reference compound,typically isoproterenol, is included in every experiment for qualitycontrol purposes.

Raw counts from scintillation counters are fit to a nonlinear leastsquares curve fitting program to obtain IC₅₀ values. Ki values aredetermined from IC₅₀ values using the Cheng-Prusoff equation and theradioligand Kd. Mean Ki values and 95% confidence intervals arecalculated from the mean log(Ki) value.

Example 4 Beta-3 Adrenergic Receptor Antagonists in Normal and ChronicHeart Failure Models

Beta-3 adrenergic receptor antagonists were evaluated for effects oncardiac contractility in normal and chronic heart failure (CHF) rats.Because beta-3 adrenergic receptor expression is weak in the normal ratheart, compounds were evaluated for the ability to attenuate thenegative contractile effects of the beta-3 adrenergic receptor agonistBRL 37344 (Tocris Bioscience, Bristol, UK) in the normal rats. Becausebeta-3 adrenergic receptor expression is higher in the rat heart withCHF, a compound was evaluated for the ability to improve contractilitycompared to baseline in this CHF rat model.

Myocardial infarction was induced in male Sprague-Dawley rats byperforming left coronary descending artery ligation. The rats wereanesthetized using an isoflurane vaporizer (Summit Medical; 5% inductionand 2-3% during the surgery), intubated, and placed on a ventilator(Cat. #55-0000, Harvard Apparatus, Holliston, Mass.) supplying 2-3%isoflurane in oxygen at a tidal volume of 2.5 mL/stroke at a rate of 70strokes per minute. A 2-cm incision was made to open the chest with ahemostat. The left coronary descending artery was ligated with a 7-0Prolene suture 3 mm from origin of the left coronary descending artery.The chest was then closed using 4-0 silk suture (Cat #1677G, Ethicon,Somerville, N.J.), and the rats were taken off the ventilator and placedin a home cage following spontaneous breathing.

Heart failure was evaluated weekly following surgery by testing impairedleft ventricular function by echocardiography. Left ventricleend-diastolic volume (LVEDV) and left ventricle end-systolic volume(LVESV) were measured for at least three consecutive cardiac cycles inlong-axis view images. Ejection Fraction (EF %) was calculated using thefollowing formula: EF %=(LVEDV−LVESV)/LVEDV. An ejection fraction<30%was used at the cutoff for heart failure.

A direct determination of left ventricular function was used for allrats to evaluate the effects of compounds on left ventricularcontractility. Right carotid artery catheterization was used forcontractility measurements. The rats were anesthetized with anintraperitoneal injection of INACTIN® (Cat #T-133, Sigma, St. Louis,Mo.) (100 mg/kg body weight), and a Millar MIKRO-TIP® pressure catheter(Cat #SPR-320NR, Millar, Inc., Houston, Tex.) was passed through thecarotid artery into left ventricle. Left ventricular pressure (LVP) wasmonitored by LabChart with POWERLAB® Data Acquisition System(ADlnstruments, Sydney, Australia).

Jugular vein catheterization was used for compound administration. Asilastic catheter (Cat #427411, BD, Franklin Lakes, N.J.) was introducedinto the jugular vein, and a right venous catheter was connected to anautomated drug delivery system (11 Plus Syringe Pump, Harvard Apparatus,Holliston, Mass.).

In the normal rats, 3 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg of testcompounds were administered starting 30-45 minutes after catheterimplantation. A bolus injection of BRL 37344 (3 μg/kg) was administeredvia the left jugular vein 15-20 minutes after test compound infusion wasstarted, and five minutes before compound infusion was stopped. A bloodsample (800 μl) was then taken from the left venous catheter fiveminutes after the bolus injection of BRL 37344 (FIG. 25).

Development of CHF was monitored by echocardiography in rats after thesurgically-induced myocardial infarction. When the EF % fell below 30%(typically 3-5 months following artery ligation), each animal wasprepared for drug testing. Vehicle was administered for 10 minutesfollowing stabilization. Test compound was then administered for 10minutes at 10 mg/kg, followed by 10 minutes at 30 mg/kg. A blood sample(800 microliters whole blood) was then taken from the left venouscatheter immediately following each 10-minute drug infusion to monitorplasma concentrations of test compound (FIG. 26).

Compound 123 (FIG. 27), Compound 310 (FIG. 28), Compound 163 (FIG. 29),Compound 154 (FIG. 30), and Compound 88 (FIG. 31) dose-dependentlyinhibited the negative effect of beta-3 adrenergic receptor agonist BRLon LVP in normal rats. In addition, Compound 88 demonstrated a trendtoward improved contractility with increased dosage in a rat with CHF(FIG. 32).

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention.

The invention claimed is:
 1. A compound that is a hydrate of1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 310).
 2. A compound that is a hydrate of3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one(Compound 326).
 3. A compound that is a hydrate of3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethyl-8-fluoroquinolin-4(1H)-one(Compound 333).
 4. A method for treating heart failure in an individual,comprising administering to said individual in need thereof atherapeutically effective amount of a compound according to claim
 1. 5.A method for treating heart failure in an individual, comprisingadministering to said individual in need thereof a therapeuticallyeffective amount of a compound according to claim
 2. 6. A method fortreating heart failure in an individual, comprising administering tosaid individual in need thereof a therapeutically effective amount of acompound according to claim 3.